Is ATOX1 p.Pro2Ser (c.4C>T) pathogenic?

ATOX1 p.Pro2Ser (c.4C>T) is classified Uncertain significance in ATOX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-04). AlphaMissense: likely benign (0.1127); Very rare (popmax 0.00526%, amr).

How common is ATOX1 p.Pro2Ser (c.4C>T) in the general population?

ATOX1 p.Pro2Ser (c.4C>T) is very rare (popmax 0.00526%, amr) (gnomAD).

What do computational predictors say about ATOX1 p.Pro2Ser (c.4C>T)?

AlphaMissense predicts likely benign (score 0.1127) — an in-silico prediction, not a clinical call.

ATOX1 p.Pro2Ser

c.4C>T · VCV4171697

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1127 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00526%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1127	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 12 kb · p 0.13 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00526% Admixed American · 2/38,016 alleles

Filtering AF 0.000872% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000326%

Overall 0.000309% 4/1,294,508 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00526%	19,008
European (non-Finnish)	0.000183%	547,678

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: ATOX1
Protein: p.Pro2Ser
Coding: c.4C>T
MANE Select: NM_004045
Type: single nucleotide variant
Location: chr5:151758548 (GRCh38)
Gene constraint: LOEUF 1.361 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 97.62 · 17 PDB
Residue 2: the hma domain

Full ATOX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATOX1 p.Asp34Glu Uncertain significance ★ ⚠ same type
ATOX1 p.Glu5Lys Uncertain significance ★ ⚠ same type
ATOX1 p.Leu26Phe Uncertain significance ★ ⚠ same type
ATOX1 p.Lys39Glu Uncertain significance ★ ⚠ same type
ATOX1 p.Lys56Arg Uncertain significance ★ ⚠ same type
ATOX1 p.Thr50Asn Uncertain significance ★ ⚠ same type
ATOX1 p.Val19Leu 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/atox1-p-pro2ser (accessed [today's date]).

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