Is ATF6B p.Asp12Ala (c.35A>C) pathogenic?

ATF6B p.Asp12Ala (c.35A>C) is classified Uncertain significance in ATF6B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: ambiguous (0.4859); Ultra-rare (popmax 0.0112%, nfe).

How common is ATF6B p.Asp12Ala (c.35A>C) in the general population?

ATF6B p.Asp12Ala (c.35A>C) is ultra-rare (popmax 0.0112%, nfe) (gnomAD).

What do computational predictors say about ATF6B p.Asp12Ala (c.35A>C)?

AlphaMissense predicts ambiguous (score 0.4859) — an in-silico prediction, not a clinical call.

ATF6B p.Asp12Ala

c.35A>C · VCV4162275

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4859 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4859	ambiguous
REVEL	0.179	moderately benign-leaning
SaProt	LLR -8.32	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 7.8	GERP 4.4, phastCons 1
Overall
CADD	25.4	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 0.0112% European (non-Finnish) · 132/1,179,790 alleles

Filtering AF 0.00961% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00904%

Overall 0.00844% 136/1,612,272 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0112%	8,938
Remaining individualsnot grpmax-eligible	0.0048%	20,820
African / African-American	0.00134%	74,686

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: ATF6B
Protein: p.Asp12Ala
Coding: c.35A>C
MANE Select: NM_004381
Type: single nucleotide variant
Location: chr6:32128173 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.31
Residue 12: the 'transcription activation' region

Full ATF6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATF6B p.His601Leu Likely benign ★★ same type
ATF6B p.Ala11Thr Uncertain significance ★ ⚠ same type
ATF6B p.Ala236Asp Uncertain significance ★ ⚠ same type
ATF6B p.Ala2Thr Uncertain significance ★ ⚠ same type
ATF6B p.Ala2Val Uncertain significance ★ ⚠ same type
ATF6B p.Ala422Val Uncertain significance ★ ⚠ same type
ATF6B p.Ala686Glu Uncertain significance ★ ⚠ same type
ATF6B p.Ala686Val Uncertain significance ★ ⚠ 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/atf6b-p-asp12ala (accessed [today's date]).

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