Is ACTR1B p.Ser331Leu (c.992C>T) pathogenic?

ACTR1B p.Ser331Leu (c.992C>T) is classified Uncertain significance in ACTR1B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely benign (0.1795); Ultra-rare (popmax 0.0233%, amr).

How common is ACTR1B p.Ser331Leu (c.992C>T) in the general population?

ACTR1B p.Ser331Leu (c.992C>T) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about ACTR1B p.Ser331Leu (c.992C>T)?

AlphaMissense predicts likely benign (score 0.1795) — an in-silico prediction, not a clinical call.

ACTR1B p.Ser331Leu

c.992C>T · rs765785816 · VCV2362928

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1795 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1795	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.65, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,029 bp · p 0.024 · regional, not allelic
Overall
CADD	22.3	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0233% Admixed American · 14/59,958 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.0036% 58/1,613,320 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,283
Middle Eastern	0.0173%	5,766
Remaining individualsnot grpmax-eligible	0.00481%	20,811
European (non-Finnish)	0.00331%	30,250
African / African-American	0.00133%	75,034

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: ACTR1B
Protein: p.Ser331Leu
Coding: c.992C>T
MANE Select: NM_005735
dbSNP: rs765785816
Type: single nucleotide variant
Location: chr2:97657188 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.34

Full ACTR1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTR1B p.Phe211Leu Uncertain significance ★★ ⚠ same type
ACTR1B p.Ala124Val Uncertain significance ★ ⚠ same type
ACTR1B p.Ala149Thr Uncertain significance ★ ⚠ same type
ACTR1B p.Ala209Pro Uncertain significance ★ ⚠ same type
ACTR1B p.Arg188Cys Uncertain significance ★ ⚠ same type
ACTR1B p.Arg188His Uncertain significance ★ ⚠ same type
ACTR1B p.Arg192Cys Uncertain significance ★ ⚠ same type
ACTR1B p.Arg192His 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/actr1b-p-ser331leu (accessed [today's date]).

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