Is ACTL7A p.Phe316Cys (c.947T>G) pathogenic?

ACTL7A p.Phe316Cys (c.947T>G) is classified Uncertain significance in ACTL7A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely pathogenic (0.8519); Very rare (popmax 0.00668%, afr).

How common is ACTL7A p.Phe316Cys (c.947T>G) in the general population?

ACTL7A p.Phe316Cys (c.947T>G) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about ACTL7A p.Phe316Cys (c.947T>G)?

AlphaMissense predicts likely pathogenic (score 0.8519) — an in-silico prediction, not a clinical call.

ACTL7A p.Phe316Cys

c.947T>G · VCV4001801

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8519 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8519	likely pathogenic
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -12.38	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 4.2	GERP 0.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,304 bp · p 0.81 · regional, not allelic
Overall
CADD	25.2	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 0.00668% African / African-American · 5/74,888 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00335% 54/1,612,842 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,978
European (non-Finnish)	0.00399%	25,085
East Asian	0.00223%	44,878
South Asian	0.0011%	91,066

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: ACTL7A
Protein: p.Phe316Cys
Coding: c.947T>G
MANE Select: NM_006687
Type: single nucleotide variant
Location: chr9:108863269 (GRCh38)
Gene constraint: LOEUF 1.182 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.81 · 1 PDB
Residue 316: a UniProt-annotated variant site (in spgf86; likely pathogenic); a UniProt-annotated variant site (in spgf86; likely pathogenic; loss of protein expression in patient sperm)

Full ACTL7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTL7A p.Phe316Val Uncertain significance ★ ⚠ same residue
ACTL7A p.Arg373His Likely pathogenic ★ same type
ACTL7A p.Gly402Ser Likely pathogenic ★ same type
ACTL7A p.Ala166Glu Uncertain significance ★ ⚠ same type
ACTL7A p.Ala166Val Uncertain significance ★ ⚠ same type
ACTL7A p.Ala190Asp Uncertain significance ★ ⚠ same type
ACTL7A p.Ala27Asp Uncertain significance ★ ⚠ same type
ACTL7A p.Ala86Gly 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/actl7a-p-phe316cys (accessed [today's date]).

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