Is MYO7A p.Leu2174Phe (c.6522G>C) pathogenic?

MYO7A p.Leu2174Phe (c.6522G>C) is classified Uncertain significance in MYO7A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.9407); Very rare (popmax 0.00666%, amr).

How common is MYO7A p.Leu2174Phe (c.6522G>C) in the general population?

MYO7A p.Leu2174Phe (c.6522G>C) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about MYO7A p.Leu2174Phe (c.6522G>C)?

AlphaMissense predicts likely pathogenic (score 0.9407) — an in-silico prediction, not a clinical call.

MYO7A p.Leu2174Phe

c.6522G>C · rs1481841012 · VCV1982099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9407 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9407	likely pathogenic
REVEL	0.708	pathogenic-leaning
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.20	donor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.3	GERP 0.85, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	24.8	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 0.00666% Admixed American · 4/60,016 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000558% 9/1,613,956 alleles · very rare exomes 6/1,461,700 · genomes 3/152,256 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,004
European (non-Finnish)	0.000424%	235,984

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.Leu2174Phe
Coding: c.6522G>C
MANE Select: NM_000260
dbSNP: rs1481841012
Type: single nucleotide variant
Location: chr11:77213943 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 2174: the ferm 2 domain

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

Similar variants

MYO7A p.Leu2174Trp Uncertain significance ★★ ⚠ same residue
MYO7A p.Leu2174= Likely benign ★★ same residue
MYO7A p.Leu2174Ser Uncertain significance ★ ⚠ 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

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-leu2174phe (accessed [today's date]).

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