Is ATF6 p.Met129Arg (c.386T>G) pathogenic?

ATF6 p.Met129Arg (c.386T>G) is classified Uncertain significance in ATF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-18). AlphaMissense: likely benign (0.1893); Very rare (popmax 0.00771%, sas); Associated with Inborn genetic diseases.

What condition is associated with ATF6 p.Met129Arg (c.386T>G)?

ATF6 p.Met129Arg (c.386T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ATF6 p.Met129Arg (c.386T>G) in the general population?

ATF6 p.Met129Arg (c.386T>G) is very rare (popmax 0.00771%, sas) (gnomAD).

What do computational predictors say about ATF6 p.Met129Arg (c.386T>G)?

AlphaMissense predicts likely benign (score 0.1893) — an in-silico prediction, not a clinical call.

ATF6 p.Met129Arg

c.386T>G · rs150831546 · VCV2327964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00771%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1893	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -6.33	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 3.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	18.94	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 0.00771% South Asian · 7/90,796 alleles

Filtering AF 0.0036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00124% 20/1,611,830 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00771%	12,971
Remaining individualsnot grpmax-eligible	0.0016%	62,428
European (non-Finnish)	0.00102%	98,280

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: ATF6
Protein: p.Met129Arg
Coding: c.386T>G
MANE Select: NM_007348
dbSNP: rs150831546
Type: single nucleotide variant
Location: chr1:161791439 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 129: the 'transcription activation' region; the 'disordered' region

Full ATF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ATF6 p.Met129Val Benign/Likely benign ★★ same residue
ATF6 p.Ala188Gly Uncertain significance ★★ ⚠ same condition
ATF6 p.Ala189Val Uncertain significance ★★ ⚠ same condition
ATF6 p.Ala226Glu Uncertain significance ★★ ⚠ same condition
ATF6 p.Ala336Val Uncertain significance ★★ ⚠ same condition
ATF6 p.Ala5Thr Uncertain significance ★★ ⚠ same condition
ATF6 p.Arg106Pro Uncertain significance ★★ ⚠ same condition
ATF6 p.Arg357Gln Uncertain significance ★★ ⚠ same condition

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/atf6-p-met129arg (accessed [today's date]).

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