Is ATF4 p.Arg342Cys (c.1024C>T) pathogenic?

ATF4 p.Arg342Cys (c.1024C>T) is classified Uncertain significance in ATF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely benign (0.2242); Very rare (popmax 0.00449%, eas).

How common is ATF4 p.Arg342Cys (c.1024C>T) in the general population?

ATF4 p.Arg342Cys (c.1024C>T) is very rare (popmax 0.00449%, eas) (gnomAD).

What do computational predictors say about ATF4 p.Arg342Cys (c.1024C>T)?

AlphaMissense predicts likely benign (score 0.2242) — an in-silico prediction, not a clinical call.

ATF4 p.Arg342Cys

c.1024C>T · VCV3442295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2242 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2242	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -9.97	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 1.8	GERP 1.9, phastCons 0.94
Regional constraint	o/e 1.29	unconstrained · MANE · 1,153 bp · p 2.5e-09 · regional, not allelic
Overall
CADD	27.3	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 0.00449% East Asian · 2/44,508 alleles

Filtering AF 0.00305% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00273%

Overall 0.00463% 72/1,555,524 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0291%	3,441
Remaining individualsnot grpmax-eligible	0.00835%	11,979
East Asiangrpmax	0.00449%	22,254
European (non-Finnish)	0.00398%	25,119
South Asian	0.00123%	81,270

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg342Cys
Coding: c.1024C>T
MANE Select: NM_182810
Type: single nucleotide variant
Location: chr22:39522570 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 62.95 · 2 PDB

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-arg342cys (accessed [today's date]).

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