Is MYO7A p.Thr2109Ile (c.6326C>T) pathogenic?

MYO7A p.Thr2109Ile (c.6326C>T) is classified Likely pathogenic in MYO7A (ClinVar, Expert panel, 6 submitters; last evaluated 2023-01-18). AlphaMissense: likely pathogenic (0.9536); Very rare (popmax 0.00636%, nfe); Associated with Usher syndrome.

What condition is associated with MYO7A p.Thr2109Ile (c.6326C>T)?

MYO7A p.Thr2109Ile (c.6326C>T) is associated with Usher syndrome (ClinVar).

How common is MYO7A p.Thr2109Ile (c.6326C>T) in the general population?

MYO7A p.Thr2109Ile (c.6326C>T) is very rare (popmax 0.00636%, nfe) (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.Thr2109Ile (c.6326C>T)?

AlphaMissense predicts likely pathogenic (score 0.9536) — an in-silico prediction, not a clinical call.

MYO7A p.Thr2109Ile

c.6326C>T · rs377670513 · VCV164724

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome

ClinGen expert panel — Hearing Loss VCEP

Likely Pathogenic for Usher syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting PP1_Moderate PM3_Strong PP3 PP4

Curation rationale (ClinGen, verbatim)

The variant NM_000260.4:c.6326C>T in MYO7A is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 2109 (p.Thr2109Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (8/128408 alleles, 0 homozygotes) for the European (Non-Finnish) population, which meets PM2_supporting criteria. The REVEL computational prediction analysis tool produced a score of 0.821, meeting PP3 criteria. This variant has been reported in two unrelated probands, both with Usher syndrome (PP4; SCV000199631.4). In addition, both probands had an additional MYO7A pathogenic or likely pathogenic variant in trans, meeting PM3_Strong criteria. Finally, the variant was shown to segregate with two affected family members (PP1_Moderate). In summary, the variant meets criteria to be classified as likely pathogenic for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: PM2_supporting, PP3, PP4, PM3_Strong, PP1_Moderate (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023).

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

Computational evidence

Protein change
AlphaMissense	0.9536	likely pathogenic ✓ concordant with ClinVar
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00636% European (non-Finnish) · 75/1,179,846 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00483% 78/1,613,830 alleles · very rare exomes 73/1,461,628 · genomes 5/152,202 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00636%	15,731
African / African-American	0.00267%	37,465
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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.Thr2109Ile
Coding: c.6326C>T
MANE Select: NM_000260
dbSNP: rs377670513
Type: single nucleotide variant
Location: chr11:77211909 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 2109: the ferm 2 domain; a turn

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

For Usher syndrome (Orphanet):

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

Similar variants

MYO7A p.Thr2109Ser Uncertain significance ★★ same residue
MYO7A p.Thr2109Pro Uncertain significance ⚠ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg668Cys Pathogenic ★★★ same condition
MYO7A p.Gly2187Asp Likely pathogenic ★★★ same condition
MYO7A p.His133Asn 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-thr2109ile (accessed [today's date]).

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