Is MYO7A p.Ser1276Leu (c.3827C>T) pathogenic?

MYO7A p.Ser1276Leu (c.3827C>T) is classified Uncertain significance in MYO7A (ClinVar, Expert panel, 6 submitters; last evaluated 2023-01-24). AlphaMissense: likely pathogenic (0.9738); Very rare (popmax 0.00346%, amr); Associated with Usher syndrome.

What condition is associated with MYO7A p.Ser1276Leu (c.3827C>T)?

MYO7A p.Ser1276Leu (c.3827C>T) is associated with Usher syndrome, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Ser1276Leu (c.3827C>T) in the general population?

MYO7A p.Ser1276Leu (c.3827C>T) is very rare (popmax 0.00346%, amr) (gnomAD).

How is Usher syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MYO7A p.Ser1276Leu (c.3827C>T)?

AlphaMissense predicts likely pathogenic (score 0.9738) — an in-silico prediction, not a clinical call.

MYO7A p.Ser1276Leu

c.3827C>T · rs369458838 · VCV178283

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00346%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome

ClinGen expert panel — Hearing Loss VCEP

Uncertain Significance for Usher syndrome. Applied ACMG criteria (verbatim):

PP3 PM3

Curation rationale (ClinGen, verbatim)

The NM_000260.4:c.3827C>T variant in the MYO7A gene is a missense variant predicted to cause substitution of serine to leucine at amino acid 1276 (p.Ser1276Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0078% (1/12706) in African/African American population ( PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in 1 patient with hearing loss in trans with a likely pathogenic variant (PM3; Partners LMM internal data SCV000204707.4). The computational predictor REVEL gives a score of 0.769, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM3, PP3. (VCEP specifications version 2.0.0; Dec 21, 2022)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9738	likely pathogenic
REVEL	0.769	pathogenic-leaning
SaProt	LLR -15.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00346% Admixed American · 2/57,772 alleles

Filtering AF 0.000574% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000215%

Overall 0.000438% 7/1,597,322 alleles · very rare exomes 5/1,445,242 · genomes 2/152,080 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00346%	28,886
African / African-American	0.00269%	37,230
East Asian	0.00227%	44,086
South Asian	0.00114%	87,778
European (non-Finnish)	8.53e-05%	1,172,418

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MYO7A
Protein: p.Ser1276Leu
Coding: c.3827C>T
MANE Select: NM_000260
dbSNP: rs369458838
Type: single nucleotide variant
Location: chr11:77190773 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1276: the ferm 1 domain

Full MYO7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usher syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 autosomal recessive nonsyndromic hearing loss 2

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

MYO7A p.Ser1276= Likely benign ★ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Arg668Cys Pathogenic ★★★ same condition
MYO7A p.Arg853His Likely pathogenic ★★★ same condition
MYO7A p.Glu968Asp Likely pathogenic ★★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/myo7a-p-ser1276leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown