Is ACTL7B p.Pro142Ala (c.424C>G) pathogenic?

ACTL7B p.Pro142Ala (c.424C>G) is classified Uncertain significance in ACTL7B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.1508); Very rare (popmax 0.00136%, nfe).

How common is ACTL7B p.Pro142Ala (c.424C>G) in the general population?

ACTL7B p.Pro142Ala (c.424C>G) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about ACTL7B p.Pro142Ala (c.424C>G)?

AlphaMissense predicts likely benign (score 0.1508) — an in-silico prediction, not a clinical call.

ACTL7B p.Pro142Ala

c.424C>G · rs1165083441 · VCV2250124

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1508 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1508	likely benign
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -10.86	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,244 bp · p 0.29 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,180,054 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00105% 17/1,613,466 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00136%	73,753
African / African-American	0.00133%	74,942

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: ACTL7B
Protein: p.Pro142Ala
Coding: c.424C>G
MANE Select: NM_006686
dbSNP: rs1165083441
Type: single nucleotide variant
Location: chr9:108855507 (GRCh38)
Gene constraint: LOEUF 1.414 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.35

Full ACTL7B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTL7B p.Ala263= Benign ★★ same type
ACTL7B p.Ala164Thr Uncertain significance ★ ⚠ same type
ACTL7B p.Ala240Val Uncertain significance ★ ⚠ same type
ACTL7B p.Ala243Thr Uncertain significance ★ ⚠ same type
ACTL7B p.Ala28Val Uncertain significance ★ ⚠ same type
ACTL7B p.Ala2Val Uncertain significance ★ ⚠ same type
ACTL7B p.Ala36Gly Uncertain significance ★ ⚠ same type
ACTL7B p.Ala388Ser 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/actl7b-p-pro142ala (accessed [today's date]).

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