Is MYO7A p.Arg858Leu (c.2573G>T) pathogenic?

MYO7A p.Arg858Leu (c.2573G>T) is classified Uncertain significance in MYO7A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: ambiguous (0.4264); Ultra-rare (popmax 0.0222%, mid).

How common is MYO7A p.Arg858Leu (c.2573G>T) in the general population?

MYO7A p.Arg858Leu (c.2573G>T) is ultra-rare (popmax 0.0222%, mid) (gnomAD).

What do computational predictors say about MYO7A p.Arg858Leu (c.2573G>T)?

AlphaMissense predicts ambiguous (score 0.4264) — an in-silico prediction, not a clinical call.

MYO7A p.Arg858Leu

c.2573G>T · rs782428224 · VCV1350022

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4264 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0222%, mid)

Computational evidence

Protein change
AlphaMissense	0.4264	ambiguous
REVEL	0.561	indeterminate
SaProt	LLR -10.18	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	25.9	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 0.0222% Middle Eastern · 1/4,502 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0089%

Overall 0.00144% 22/1,526,890 alleles · ultra-rare exomes 21/1,374,616 · genomes 1/152,274 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0222%	4,502
South Asian	0.0179%	5,575
Remaining individualsnot grpmax-eligible	0.00169%	59,228
European (non-Finnish)	0.000439%	227,678

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.Arg858Leu
Coding: c.2573G>T
MANE Select: NM_000260
dbSNP: rs782428224
Type: single nucleotide variant
Location: chr11:77179940 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 858: the 'sah' region

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

Similar variants

MYO7A p.Arg858Cys Uncertain significance ★★ same residue
MYO7A p.Arg858His Conflicting classifications of pathogenicity ★ ⚠ same residue
MYO7A p.Arg858= 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

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-arg858leu (accessed [today's date]).

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