Is MYO7A p.Arg623Leu (c.1868G>T) pathogenic?

MYO7A p.Arg623Leu (c.1868G>T) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-17). AlphaMissense: likely pathogenic (0.5721); Ultra-rare (popmax 0.0742%, amr); Associated with Usher syndrome type 1B.

What condition is associated with MYO7A p.Arg623Leu (c.1868G>T)?

MYO7A p.Arg623Leu (c.1868G>T) is associated with Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Arg623Leu (c.1868G>T) in the general population?

MYO7A p.Arg623Leu (c.1868G>T) is ultra-rare (popmax 0.0742%, amr) (gnomAD).

What do computational predictors say about MYO7A p.Arg623Leu (c.1868G>T)?

AlphaMissense predicts likely pathogenic (score 0.5721) — an in-silico prediction, not a clinical call.

MYO7A p.Arg623Leu

c.1868G>T · rs111033416 · VCV848327

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.5721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0742%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Usher syndrome type 1B

Computational evidence

Protein change
AlphaMissense	0.5721	likely pathogenic
REVEL	0.621	indeterminate
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	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 0.0742% Admixed American · 38/51,214 alleles

Filtering AF 0.0555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.049%

Overall 0.00328% 51/1,553,612 alleles · ultra-rare exomes 21/1,401,260 · genomes 30/152,352 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0742%	1,348
Remaining individualsnot grpmax-eligible	0.0116%	8,605
African / African-American	0.00273%	36,624
South Asian	0.00238%	42,054
European (non-Finnish)	0.000174%	574,181

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.Arg623Leu
Coding: c.1868G>T
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

Usher syndrome type 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MYO7A p.Arg623His Conflicting classifications of pathogenicity ★ ⚠ 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-arg623leu (accessed [today's date]).

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