Is ATF4 p.Pro258Ala (c.772C>G) pathogenic?

ATF4 p.Pro258Ala (c.772C>G) is classified Benign in ATF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0891); Low-frequency (popmax 4.6%, afr).

How common is ATF4 p.Pro258Ala (c.772C>G) in the general population?

ATF4 p.Pro258Ala (c.772C>G) is low-frequency (popmax 4.6%, afr) (gnomAD).

What do computational predictors say about ATF4 p.Pro258Ala (c.772C>G)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

ATF4 p.Pro258Ala

c.772C>G · rs1803323 · VCV780657

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.6%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -7.14	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 2.2	GERP -1.6, phastCons 0.97
Regional constraint	o/e 1.29	unconstrained · MANE · 1,153 bp · p 2.5e-09 · regional, not allelic
Overall
CADD	20.7	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

Grpmax group 4.6% African / African-American · 3,448/74,902 alleles

Filtering AF 4.48% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.42%

Overall 0.238% 3,843/1,612,688 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.6%	22
Remaining individualsnot grpmax-eligible	0.291%	343
Admixed American	0.254%	393
Middle Eastern	0.0991%	1,009
South Asian	0.00771%	12,964
European (non-Finnish)	0.00407%	24,571

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: ATF4
Protein: p.Pro258Ala
Coding: c.772C>G
MANE Select: NM_182810
dbSNP: rs1803323
Type: single nucleotide variant
Location: chr22:39522318 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 62.95 · 2 PDB
Residue 258: the 'disordered' region; a UniProt-annotated variant site (in)

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

Similar variants

ATF4 p.Pro258Leu Uncertain significance ★ ⚠ same residue
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.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-pro258ala (accessed [today's date]).

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