Is ATF1 p.Met136Val (c.406A>G) pathogenic?

ATF1 p.Met136Val (c.406A>G) is classified Uncertain significance in ATF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). AlphaMissense: likely benign (0.1433); Very rare (popmax 0.00483%, nfe).

How common is ATF1 p.Met136Val (c.406A>G) in the general population?

ATF1 p.Met136Val (c.406A>G) is very rare (popmax 0.00483%, nfe) (gnomAD).

What do computational predictors say about ATF1 p.Met136Val (c.406A>G)?

AlphaMissense predicts likely benign (score 0.1433) — an in-silico prediction, not a clinical call.

ATF1 p.Met136Val

c.406A>G · VCV3959595

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1433 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00483%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1433	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -5.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.4, phastCons 1
Overall
CADD	22.8	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 0.00483% European (non-Finnish) · 57/1,180,044 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00359% 58/1,614,094 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00483%	20,703
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: ATF1
Protein: p.Met136Val
Coding: c.406A>G
MANE Select: NM_000514 · reported on NM_005171
Type: single nucleotide variant
Location: chr12:50814087 (GRCh38)
Structure: AlphaFold pLDDT 75.29 · 4 PDB
Residue 136: a disulfide bond

Full ATF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATF1 p.Met136Ile Uncertain significance ★ ⚠ same residue
ATF1 p.Met136Lys Uncertain significance ★ ⚠ same residue
GDNF c.*2213G>A Uncertain significance ★★ same type
GDNF c.*2828T>A Uncertain significance ★★ same type
GDNF p.Arg116Gln Uncertain significance ★★ ⚠ same type
ATF1 p.Tyr109= Benign ★★ same type
ATF2 p.Asn348= Benign ★★ same type
ATF2 p.Asp440= 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/atf1-p-met136val (accessed [today's date]).

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