Is ACTL7A p.Pro194Ser (c.580C>T) pathogenic?

ACTL7A p.Pro194Ser (c.580C>T) is classified Uncertain significance in ACTL7A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.7088); Absent from gnomAD v4.1.

How common is ACTL7A p.Pro194Ser (c.580C>T) in the general population?

ACTL7A p.Pro194Ser (c.580C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTL7A p.Pro194Ser (c.580C>T)?

AlphaMissense predicts likely pathogenic (score 0.7088) — an in-silico prediction, not a clinical call.

ACTL7A p.Pro194Ser

c.580C>T · VCV4221326

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7088 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7088	likely pathogenic
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2, 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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTL7A
Protein: p.Pro194Ser
Coding: c.580C>T
MANE Select: NM_006687
Type: single nucleotide variant
Location: chr9:108862902 (GRCh38)
Gene constraint: LOEUF 1.182 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.81 · 1 PDB
Residue 194: 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.Pro194Ala 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-pro194ser (accessed [today's date]).

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