Is MYO7A p.Leu375Phe (c.1123C>T) pathogenic?

MYO7A p.Leu375Phe (c.1123C>T) is classified Conflicting classifications of pathogenicity in MYO7A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-19). AlphaMissense: likely pathogenic (0.6627); Ultra-rare (popmax 0.0108%, afr).

How common is MYO7A p.Leu375Phe (c.1123C>T) in the general population?

MYO7A p.Leu375Phe (c.1123C>T) is ultra-rare (popmax 0.0108%, afr) (gnomAD).

What do computational predictors say about MYO7A p.Leu375Phe (c.1123C>T)?

AlphaMissense predicts likely pathogenic (score 0.6627) — an in-silico prediction, not a clinical call.

MYO7A p.Leu375Phe

c.1123C>T · rs782728522 · VCV2188416

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6627 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6627	likely pathogenic
REVEL	0.446	indeterminate
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	GERP -3.2, phastCons 0.98
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	23.2	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 0.0108% African / African-American · 8/74,056 alleles

Filtering AF 0.00533% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00384%

Overall 0.000886% 14/1,580,244 alleles · ultra-rare exomes 9/1,428,028 · genomes 5/152,216 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0108%	9,257
South Asian	0.00699%	14,302

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.Leu375Phe
Coding: c.1123C>T
MANE Select: NM_000260
dbSNP: rs782728522
Type: single nucleotide variant
Location: chr11:77160205 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 375: the myosin motor domain

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

Similar variants

MYO7A p.Leu375Val Uncertain significance ★ ⚠ same residue
MYO7A p.Leu375= Likely benign ★ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same type
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same type
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same type
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same type
MYO7A p.Arg668Cys Pathogenic ★★★ same type
MYO7A p.Arg853His Likely pathogenic ★★★ same type

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-leu375phe (accessed [today's date]).

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