Is ATF4 p.Pro249Ser (c.745C>T) pathogenic?

ATF4 p.Pro249Ser (c.745C>T) is classified Uncertain significance in ATF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.0802); Absent from gnomAD v4.1.

How common is ATF4 p.Pro249Ser (c.745C>T) in the general population?

ATF4 p.Pro249Ser (c.745C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATF4 p.Pro249Ser (c.745C>T)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

ATF4 p.Pro249Ser

c.745C>T · VCV4161996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -7.15	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 -0.009	GERP 0.64
Regional constraint	o/e 1.29	unconstrained · MANE · 1,153 bp · p 2.5e-09 · regional, not allelic
Overall
CADD	14.53	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

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: ATF4
Protein: p.Pro249Ser
Coding: c.745C>T
MANE Select: NM_182810
Type: single nucleotide variant
Location: chr22:39522291 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 62.95 · 2 PDB
Residue 249: the 'disordered' region

Full ATF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATF4 p.Ala324Val Benign ★★ same type
ATF4 p.Asn131= Benign ★★ same type
ATF4 p.Glu322Asp Benign ★★ ⚠ same type
ATF4 p.Glu3Lys Benign ★★ ⚠ same type
ATF4 p.Ile208Met Likely benign ★★ ⚠ same type
ATF4 p.Pro258Ala Benign ★★ same type
ATF4 p.Thr137Ser Likely benign ★★ same type
ATF4 p.Tyr200= Benign ★★ 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/atf4-p-pro249ser (accessed [today's date]).

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