Is MYO7A p.Leu1954Ile (c.5860C>A) pathogenic?

MYO7A p.Leu1954Ile (c.5860C>A) is classified Benign/Likely benign in MYO7A (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.037); Common (popmax 70%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Usher syndrome type 1.

What condition is associated with MYO7A p.Leu1954Ile (c.5860C>A)?

MYO7A p.Leu1954Ile (c.5860C>A) is associated with Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2, autosomal dominant nonsyndromic hearing loss 11 (ClinVar).

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.Leu1954Ile (c.5860C>A)?

AlphaMissense predicts likely benign (score 0.037) — an in-silico prediction, not a clinical call.

MYO7A p.Leu1954Ile

Q: How common is MYO7A p.Leu1954Ile (c.5860C>A) in the general population?

MYO7A p.Leu1954Ile (c.5860C>A) is common (popmax 70%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.5860C>A · rs948962 · VCV43304

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.037 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 70%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.037	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -1.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 0.58, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	15.63	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 70% African / African-American · 52,286/74,712 alleles

Filtering AF 69.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 69.3%

Overall 47.2% 756,886/1,602,936 alleles · common exomes 676,045/1,451,080 · genomes 80,841/151,856 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	70%	1
Finnishnot grpmax-eligible	56.2%	2
Admixed American	54.1%	2
Middle Eastern	53.9%	2
Remaining individualsnot grpmax-eligible	47%	2
European (non-Finnish)	46.7%	2
Ashkenazi Jewishnot grpmax-eligible	44.4%	2
East Asian	32.5%	3
South Asian	31.7%	3
Amishnot grpmax-eligible	29.8%	3

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.Leu1954Ile
Coding: c.5860C>A
MANE Select: NM_000260
dbSNP: rs948962
Type: single nucleotide variant
Location: chr11:77208433 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1954: the ferm 2 domain; a β-strand; a UniProt-annotated variant site (in)

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

Disease context

Usher syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 2 autosomal dominant nonsyndromic hearing loss 11 Usher syndrome type 1B

For Usher syndrome (Orphanet):

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

Similar variants

MYO7A p.Leu1954Pro Uncertain significance ★ ⚠ same residue
MYO7A p.Leu1954Val Conflicting classifications of pathogenicity ★ ⚠ 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

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-leu1954ile (accessed [today's date]).

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