Is MYO7A p.Ala1224Thr (c.3670G>A) pathogenic?

MYO7A p.Ala1224Thr (c.3670G>A) is classified Conflicting classifications of pathogenicity in MYO7A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-09). AlphaMissense: ambiguous (0.5319); Ultra-rare (popmax 0.0203%, afr).

How common is MYO7A p.Ala1224Thr (c.3670G>A) in the general population?

MYO7A p.Ala1224Thr (c.3670G>A) is ultra-rare (popmax 0.0203%, afr) (gnomAD).

What do computational predictors say about MYO7A p.Ala1224Thr (c.3670G>A)?

AlphaMissense predicts ambiguous (score 0.5319) — an in-silico prediction, not a clinical call.

MYO7A p.Ala1224Thr

c.3670G>A · rs748928605 · VCV1305441

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5319 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, afr)

Computational evidence

Protein change
AlphaMissense	0.5319	ambiguous
REVEL	0.637	indeterminate
SaProt	LLR -8.36	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	24.7	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 0.0203% African / African-American · 15/74,058 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.01%

Overall 0.00216% 34/1,572,664 alleles · ultra-rare exomes 27/1,420,430 · genomes 7/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0203%	4,937
South Asian	0.00585%	17,100
European (non-Finnish)	0.00121%	82,846

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.Ala1224Thr
Coding: c.3670G>A
MANE Select: NM_000260
dbSNP: rs748928605
Type: single nucleotide variant
Location: chr11:77190059 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1224: the myth4 1 domain

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

Similar variants

MYO7A p.Ala1224Val Uncertain significance ★ ⚠ same residue
MYO7A p.Ala1224= 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-ala1224thr (accessed [today's date]).

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