Is MYO7A p.Arg1447Lys (c.4340G>A) pathogenic?

MYO7A p.Arg1447Lys (c.4340G>A) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-16). AlphaMissense: likely benign (0.0802); Ultra-rare (popmax 0.0165%, mid); Associated with MYO7A-related disorder.

What condition is associated with MYO7A p.Arg1447Lys (c.4340G>A)?

MYO7A p.Arg1447Lys (c.4340G>A) is associated with MYO7A-related disorder (ClinVar).

How common is MYO7A p.Arg1447Lys (c.4340G>A) in the general population?

MYO7A p.Arg1447Lys (c.4340G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MYO7A p.Arg1447Lys (c.4340G>A)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1447Lys

c.4340G>A · rs1203837704 · VCV1474148

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MYO7A-related disorder

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -5.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.65, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,074 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000187% 3/1,602,186 alleles · ultra-rare exomes 2/1,449,968 · genomes 1/152,218 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,074
European (non-Finnish)	0.00017%	587,120

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.Arg1447Lys
Coding: c.4340G>A
MANE Select: NM_000260
dbSNP: rs1203837704
Type: single nucleotide variant
Location: chr11:77197497 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1447: the ferm 1 domain

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

Disease context

MYO7A-related disorder

Similar variants

MYO7A c.133-2A>G Pathogenic ★★ same condition
MYO7A c.1344-2A>G Pathogenic ★★ same condition
MYO7A c.1690+1G>A Pathogenic/Likely pathogenic ★★ same condition
MYO7A c.18+1G>A Pathogenic/Likely pathogenic ★★ same condition
MYO7A c.19-1G>A Likely pathogenic ★★ same condition
MYO7A c.2187+1G>A Pathogenic/Likely pathogenic ★★ same condition
MYO7A c.2283-1G>A Pathogenic/Likely pathogenic ★★ same condition
MYO7A c.2694+1G>A Likely pathogenic ★★ 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-arg1447lys (accessed [today's date]).

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