Is MYO7A p.Arg1463His (c.4388G>A) pathogenic?

MYO7A p.Arg1463His (c.4388G>A) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-16). AlphaMissense: ambiguous (0.5105); Very rare (popmax 0.00667%, afr).

How common is MYO7A p.Arg1463His (c.4388G>A) in the general population?

MYO7A p.Arg1463His (c.4388G>A) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about MYO7A p.Arg1463His (c.4388G>A)?

AlphaMissense predicts ambiguous (score 0.5105) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1463His

c.4388G>A · rs558085909 · VCV1327730

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5105	ambiguous
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -11.30	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	33.0	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 0.00667% African / African-American · 5/74,936 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00143% 23/1,607,462 alleles · very rare exomes 19/1,455,140 · genomes 4/152,322 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,987
South Asian	0.00336%	29,797
East Asian	0.00224%	44,718
Remaining individualsnot grpmax-eligible	0.00161%	62,288
Finnishnot grpmax-eligible	0.00157%	63,578
European (non-Finnish)	0.00102%	98,077

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.Arg1463His
Coding: c.4388G>A
MANE Select: NM_000260
dbSNP: rs558085909
Type: single nucleotide variant
Location: chr11:77197545 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1463: the ferm 1 domain

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

Similar variants

MYO7A p.Arg1463Cys 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
MYO7A p.Arg853His Likely pathogenic ★★★ same type
MYO7A p.Glu968Asp 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-arg1463his (accessed [today's date]).

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