Is ACTG1 p.Ter376= (c.1128A>G) pathogenic?

ACTG1 p.Ter376= (c.1128A>G) is classified Benign in ACTG1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). Common (popmax 9.99%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant nonsyndromic hearing loss 20.

What condition is associated with ACTG1 p.Ter376= (c.1128A>G)?

ACTG1 p.Ter376= (c.1128A>G) is associated with autosomal dominant nonsyndromic hearing loss 20, Baraitser-winter syndrome 2 (ClinVar).

ACTG1 p.Ter376=

Q: How common is ACTG1 p.Ter376= (c.1128A>G) in the general population?

ACTG1 p.Ter376= (c.1128A>G) is common (popmax 9.99%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1128A>G · rs11549223 · VCV128269

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Common

common (popmax 9.99%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal dominant nonsyndromic hearing loss 20

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	stop-loss	predicted loss-of-function
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.8
Overall
CADD	7.487	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.99% African / African-American · 7,494/75,030 alleles

Filtering AF 9.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.72%

Overall 1.88% 30,274/1,613,942 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.99%	10
Ashkenazi Jewishnot grpmax-eligible	5%	20
Middle Eastern	2.49%	40
Remaining individualsnot grpmax-eligible	2.43%	41
East Asian	2.4%	42
Admixed American	2.25%	44
South Asian	1.7%	59
European (non-Finnish)	1.3%	77
Finnishnot grpmax-eligible	0.571%	175
Amishnot grpmax-eligible	0.329%	304

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: ACTG1
Protein: p.Ter376=
Coding: c.1128A>G
MANE Select: NM_001614
dbSNP: rs11549223
Type: single nucleotide variant
Location: chr17:81510690 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.46 (gnomAD)
Structure: AlphaFold pLDDT 95.44 · 11 PDB

Full ACTG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant nonsyndromic hearing loss 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Baraitser-winter syndrome 2

Similar variants

ACTG1 p.Ala135Val Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Ala204Gly Likely pathogenic ★★ same condition
ACTG1 p.Arg183Gln Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Arg183Trp Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Arg206Gln Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Arg210Cys Pathogenic ★★ same condition
ACTG1 p.Arg254Trp Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Arg335His Pathogenic/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/actg1-p-ter376 (accessed [today's date]).

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