Is ACTC1 p.Ala172Thr (c.514G>A) pathogenic?

ACTC1 p.Ala172Thr (c.514G>A) is classified Uncertain significance in ACTC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2011-12-28). AlphaMissense: likely pathogenic (0.8605); Very rare (popmax 8.47e-05%, nfe).

How common is ACTC1 p.Ala172Thr (c.514G>A) in the general population?

ACTC1 p.Ala172Thr (c.514G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACTC1 p.Ala172Thr (c.514G>A)?

AlphaMissense predicts likely pathogenic (score 0.8605) — an in-silico prediction, not a clinical call.

ACTC1 p.Ala172Thr

c.514G>A · rs876661340 · VCV234976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8605	likely pathogenic
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -12.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 2,113 bp · p 8.3e-37 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.84e-05% 1/1,461,888 alleles · very rare

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: ACTC1
Protein: p.Ala172Thr
Coding: c.514G>A
MANE Select: NM_005159
dbSNP: rs876661340
Type: single nucleotide variant
Location: chr15:34792510 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB

Full ACTC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTC1 p.Ala172Val Uncertain significance ★ ⚠ same residue
ACTC1 p.Ala172= Likely benign ★ same residue
ACTC1 p.Glu101Lys Pathogenic ★★★ same type
ACTC1 p.Gly345Val Uncertain significance ★★★ ⚠ same type
ACTC1 p.Pro266Leu Uncertain significance ★★★ ⚠ same type
ACTC1 p.Val56Ile Uncertain significance ★★★ ⚠ same type
ACTC1 p.Ala297Ser Pathogenic ★★ ⚠ same type
ACTC1 p.Gly247Asp Pathogenic/Likely pathogenic ★★ 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/actc1-p-ala172thr (accessed [today's date]).

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