Is ATF4 p.Ala328Val (c.983C>T) pathogenic?

ATF4 p.Ala328Val (c.983C>T) is classified Uncertain significance in ATF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: ambiguous (0.3669); Very rare (popmax 0.00443%, nfe).

How common is ATF4 p.Ala328Val (c.983C>T) in the general population?

ATF4 p.Ala328Val (c.983C>T) is very rare (popmax 0.00443%, nfe) (gnomAD).

What do computational predictors say about ATF4 p.Ala328Val (c.983C>T)?

AlphaMissense predicts ambiguous (score 0.3669) — an in-silico prediction, not a clinical call.

ATF4 p.Ala328Val

c.983C>T · VCV4161938

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00443%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3669	ambiguous
REVEL	0.112	moderately benign-leaning
SaProt	LLR -6.65	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 1,153 bp · p 2.5e-09 · regional, not allelic
Overall
CADD	24.2	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

Grpmax group 0.00443% European (non-Finnish) · 52/1,174,784 alleles

Filtering AF 0.00344% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00311%

Overall 0.00344% 55/1,600,946 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00443%	22,592
African / African-American	0.00271%	36,904
Remaining individualsnot grpmax-eligible	0.00162%	61,804

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.Ala328Val
Coding: c.983C>T
MANE Select: NM_182810
Type: single nucleotide variant
Location: chr22:39522529 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 62.95 · 2 PDB
Residue 328: the bzip domain; the 'interaction with gabbr1' region; an α-helix; the 'leucine-zipper' 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-ala328val (accessed [today's date]).

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