Is MYO7A p.Val408Met (c.1222G>A) pathogenic?

MYO7A p.Val408Met (c.1222G>A) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-26). AlphaMissense: ambiguous (0.3497); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with MYO7A p.Val408Met (c.1222G>A)?

MYO7A p.Val408Met (c.1222G>A) is associated with Inborn genetic diseases (ClinVar).

How common is MYO7A p.Val408Met (c.1222G>A) in the general population?

MYO7A p.Val408Met (c.1222G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about MYO7A p.Val408Met (c.1222G>A)?

AlphaMissense predicts ambiguous (score 0.3497) — an in-silico prediction, not a clinical call.

MYO7A p.Val408Met

c.1222G>A · rs782797465 · VCV1523828

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3497 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3497	ambiguous
REVEL	0.667	pathogenic-leaning
SaProt	LLR -7.21	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	25.3	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 0.0329% Middle Eastern · 2/6,078 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.0013% 21/1,609,492 alleles · ultra-rare exomes 20/1,457,434 · genomes 1/152,058 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,039
South Asian	0.00556%	17,985
African / African-American	0.00401%	24,943
Admixed American	0.00337%	29,650
Remaining individualsnot grpmax-eligible	0.0016%	62,342
European (non-Finnish)	0.000679%	147,272

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.Val408Met
Coding: c.1222G>A
MANE Select: NM_000260
dbSNP: rs782797465
Type: single nucleotide variant
Location: chr11:77160994 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 408: the myosin motor domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MYO7A p.Val408Leu Uncertain significance ★ same residue
MYO7A p.Ser1471Pro Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Ala1005Thr Uncertain significance ★★ ⚠ same condition
MYO7A p.Ala1203Ser Uncertain significance ★★ ⚠ same condition
MYO7A p.Ala1335Asp Uncertain significance ★★ ⚠ same condition
MYO7A p.Ala1551Val Uncertain significance ★★ ⚠ same condition
MYO7A p.Ala1563Val Uncertain significance ★★ ⚠ same condition
MYO7A p.Ala162Thr Uncertain significance ★★ ⚠ 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-val408met (accessed [today's date]).

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