Is ATF3 p.Ser12Pro (c.34T>C) pathogenic?

ATF3 p.Ser12Pro (c.34T>C) is classified Uncertain significance in ATF3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-09). AlphaMissense: likely benign (0.1162); Very rare (popmax 0.00333%, amr).

How common is ATF3 p.Ser12Pro (c.34T>C) in the general population?

ATF3 p.Ser12Pro (c.34T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ATF3 p.Ser12Pro (c.34T>C)?

AlphaMissense predicts likely benign (score 0.1162) — an in-silico prediction, not a clinical call.

ATF3 p.Ser12Pro

c.34T>C · rs751253931 · VCV2248803

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1162 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1162	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -6.25	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 6.1	GERP 2.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 4,530 bp · p 0.0084 · regional, not allelic
Overall
CADD	21.3	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 0.00333% Admixed American · 2/60,002 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000558% 9/1,614,044 alleles · very rare exomes 7/1,461,892 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,001
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000508%	196,675

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: ATF3
Protein: p.Ser12Pro
Coding: c.34T>C
MANE Select: NM_001674
dbSNP: rs751253931
Type: single nucleotide variant
Location: chr1:212615055 (GRCh38)
Gene constraint: LOEUF 0.879 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 77.45

Full ATF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATF3 p.Ala82Val Uncertain significance ★ ⚠ same type
ATF3 p.Asn168Ile Uncertain significance ★ ⚠ same type
ATF3 p.Asp69Asn Uncertain significance ★ ⚠ same type
ATF3 p.Gln115Glu Uncertain significance ★ ⚠ same type
ATF3 p.Glu32Lys Uncertain significance ★ ⚠ same type
ATF3 p.Glu80Lys Uncertain significance ★ ⚠ same type
ATF3 p.Ile171Thr Uncertain significance ★ ⚠ same type
ATF3 p.Leu146Phe 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/atf3-p-ser12pro (accessed [today's date]).

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