Is ACTG1 p.His73= (c.219T>C) pathogenic?

ACTG1 p.His73= (c.219T>C) is classified Likely benign in ACTG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-09). Very rare (popmax 0.00133%, afr); Associated with autosomal dominant nonsyndromic hearing loss 20.

How common is ACTG1 p.His73= (c.219T>C) in the general population?

ACTG1 p.His73= (c.219T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

ACTG1 p.His73=

Q: What condition is associated with ACTG1 p.His73= (c.219T>C)?

ACTG1 p.His73= (c.219T>C) is associated with autosomal dominant nonsyndromic hearing loss 20, Baraitser-winter syndrome 2 (ClinVar).

c.219T>C · rs782249707 · VCV2164665

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

autosomal dominant nonsyndromic hearing loss 20

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.58 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.7	GERP -3.8
Overall
CADD	2.181	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,042 alleles

Overall 0.000124% 2/1,614,002 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,042
South Asian	0.0011%	91,088

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.His73=
Coding: c.219T>C
MANE Select: NM_001614
dbSNP: rs782249707
Type: single nucleotide variant
Location: chr17:81512047 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.46 (gnomAD)
Structure: AlphaFold pLDDT 95.44 · 11 PDB
Residue 73: a modified residue (tele-methylhistidine)

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.His73Asp Uncertain significance ★ ⚠ same residue
ACTG1 p.His73Tyr Uncertain significance ★ same residue
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

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-his73 (accessed [today's date]).

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