Is MYO7B p.Ala1818Ser (c.5452G>T) pathogenic?

MYO7B p.Ala1818Ser (c.5452G>T) is classified Uncertain significance in MYO7B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: likely benign (0.1301); Ultra-rare (popmax 0.0251%, nfe).

How common is MYO7B p.Ala1818Ser (c.5452G>T) in the general population?

MYO7B p.Ala1818Ser (c.5452G>T) is ultra-rare (popmax 0.0251%, nfe) (gnomAD).

What do computational predictors say about MYO7B p.Ala1818Ser (c.5452G>T)?

AlphaMissense predicts likely benign (score 0.1301) — an in-silico prediction, not a clinical call.

MYO7B p.Ala1818Ser

c.5452G>T · rs372050866 · VCV2568564

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1301 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0251%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1301	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.23	GERP -0.54
Regional constraint	o/e 1.07	unconstrained · MANE · 7,741 bp · p 0.063 · regional, not allelic
Overall
CADD	8.499	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A1792S vs ClinVar A1818S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0251% European (non-Finnish) · 296/1,179,730 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.0193% 312/1,612,512 alleles · ultra-rare exomes 298/1,460,310 · genomes 14/152,202 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0251%	3,986
Remaining individualsnot grpmax-eligible	0.016%	6,243
Admixed American	0.00667%	14,993
African / African-American	0.00267%	37,461

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: MYO7B
Protein: p.Ala1818Ser
Coding: c.5452G>T
MANE Select: NM_001393586
dbSNP: rs372050866
Type: single nucleotide variant
Location: chr2:127633304 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.34 · 3 PDB
Residue 1792 UniProt numbering: the myth4 2 domain; the myth4 3 domain; the 'mediates interaction with cdhr2, cdhr5 and ush1c' region; an α-helix

Full MYO7B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MYO7B p.Ala1818Thr Uncertain significance ★ ⚠ same residue
MYO7B p.Thr349Met Uncertain significance ★★ ⚠ same type
MYO7B p.Ile1309Val Benign ★★ same type
MYO7B p.Val1556Ile Benign ★★ same type
MYO7B p.Val1876= Benign ★★ same type
MYO7B p.Ala1010Thr Uncertain significance ★ ⚠ same type
MYO7B p.Ala1092Thr Uncertain significance ★ ⚠ same type
MYO7B p.Ala1109Thr Uncertain significance ★ ⚠ 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/myo7b-p-ala1818ser (accessed [today's date]).

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