Is MYO7B p.Phe666Leu (c.1998C>A) pathogenic?

MYO7B p.Phe666Leu (c.1998C>A) is classified Uncertain significance in MYO7B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-04). AlphaMissense: likely pathogenic (0.8777); Ultra-rare (popmax 0.0187%, afr).

How common is MYO7B p.Phe666Leu (c.1998C>A) in the general population?

MYO7B p.Phe666Leu (c.1998C>A) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about MYO7B p.Phe666Leu (c.1998C>A)?

AlphaMissense predicts likely pathogenic (score 0.8777) — an in-silico prediction, not a clinical call.

MYO7B p.Phe666Leu

c.1998C>A · rs376826480 · VCV2375769

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8777 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8777	likely pathogenic · top 7% in MYO7B
REVEL	0.642	indeterminate
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.9	GERP -3.8
Regional constraint	o/e 0.94	unconstrained · MANE · 69 kb · p 0.0075 · regional, not allelic
Overall
CADD	18.11	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 0.0187% African / African-American · 14/74,844 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.000994% 16/1,609,384 alleles · ultra-rare exomes 6/1,457,216 · genomes 10/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,346
Admixed American	0.00168%	59,650
European (non-Finnish)	8.48e-05%	1,178,605

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: MYO7B
Protein: p.Phe666Leu
Coding: c.1998C>A
MANE Select: NM_001393586
dbSNP: rs376826480
Type: single nucleotide variant
Location: chr2:127592799 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.34 · 3 PDB
Residue 666: the myosin motor domain

Full MYO7B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MYO7B p.Thr349Met Uncertain significance ★★ ⚠ same type
MYO7B p.Ile1309Val Benign ★★ same type
MYO7B p.Val1556Ile Benign ★★ same type
MYO7B p.Val1876= Benign ★★ same type
MYO7B p.Ala1010Thr Uncertain significance ★ ⚠ same type
MYO7B p.Ala1092Thr Uncertain significance ★ ⚠ same type
MYO7B p.Ala1109Thr Uncertain significance ★ ⚠ same type
MYO7B p.Ala1126Thr Uncertain significance ★ ⚠ 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/myo7b-p-phe666leu (accessed [today's date]).

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