Is MYO7A p.Arg623His (c.1868G>A) pathogenic?

MYO7A p.Arg623His (c.1868G>A) is classified Conflicting classifications of pathogenicity in MYO7A (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.2063); Rare (popmax 0.308%, sas); Associated with autosomal recessive nonsyndromic hearing loss 2.

What condition is associated with MYO7A p.Arg623His (c.1868G>A)?

MYO7A p.Arg623His (c.1868G>A) is associated with autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1, autosomal dominant nonsyndromic hearing loss 11 (ClinVar).

How common is MYO7A p.Arg623His (c.1868G>A) in the general population?

MYO7A p.Arg623His (c.1868G>A) is rare (popmax 0.308%, sas) (gnomAD).

What do computational predictors say about MYO7A p.Arg623His (c.1868G>A)?

AlphaMissense predicts likely benign (score 0.2063) — an in-silico prediction, not a clinical call.

MYO7A p.Arg623His

c.1868G>A · rs111033416 · VCV43162

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2063 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.308%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal recessive nonsyndromic hearing loss 2

Computational evidence

Protein change
AlphaMissense	0.2063	likely benign
REVEL	0.472	indeterminate
SaProt	LLR -7.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.5	GERP -0.43, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	25.7	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 0.308% South Asian · 259/84,108 alleles

Filtering AF 0.277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.265%

Overall 0.0355% 551/1,553,612 alleles · rare exomes 507/1,401,260 · genomes 44/152,352 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.308%	325
Ashkenazi Jewishnot grpmax-eligible	0.157%	637
Middle Eastern	0.134%	749
Remaining individualsnot grpmax-eligible	0.0598%	1,673
African / African-American	0.0191%	5,232
European (non-Finnish)	0.0158%	6,310
Admixed American	0.0137%	7,316

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.Arg623His
Coding: c.1868G>A
MANE Select: NM_000260
dbSNP: rs111033416
Type: single nucleotide variant
Location: chr11:77172818 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 623: the myosin motor domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 autosomal dominant nonsyndromic hearing loss 11 Usher syndrome type 1B

Similar variants

MYO7A p.Arg623Leu Uncertain significance ★★ ⚠ same residue
MYO7A p.Arg623Cys Uncertain significance ★★ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Arg668Cys Pathogenic ★★★ same condition
MYO7A p.Arg853His 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-arg623his (accessed [today's date]).

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