Is ATF6 p.Ala145Pro (c.433G>C) pathogenic?

ATF6 p.Ala145Pro (c.433G>C) is classified Benign in ATF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0813); Common (popmax 38.5%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ATF6 p.Ala145Pro (c.433G>C)?

AlphaMissense predicts likely benign (score 0.0813) — an in-silico prediction, not a clinical call.

ATF6 p.Ala145Pro

Q: How common is ATF6 p.Ala145Pro (c.433G>C) in the general population?

ATF6 p.Ala145Pro (c.433G>C) is common (popmax 38.5%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.433G>C · rs2070150 · VCV1164406

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0813 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 38.5%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0813	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -4.02	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 1.5	GERP 1, phastCons 0.003
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	5.036	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 38.5% Admixed American · 23,060/59,836 alleles

Filtering AF 38.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 38%

Overall 9.02% 145,362/1,611,170 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	38.5%	3
East Asian	33.9%	3
Ashkenazi Jewishnot grpmax-eligible	10.5%	10
Remaining individualsnot grpmax-eligible	9.69%	10
Middle Eastern	9.19%	11
South Asian	8.59%	12
European (non-Finnish)	6.88%	15
Finnishnot grpmax-eligible	6.58%	15
African / African-American	5.79%	17
Amishnot grpmax-eligible	2.75%	36

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.Ala145Pro
Coding: c.433G>C
MANE Select: NM_007348
dbSNP: rs2070150
Type: single nucleotide variant
Location: chr1:161791486 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 145: a UniProt-annotated variant site (in); the 'transcription activation' region; the 'disordered' region

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

Similar variants

ATF6 p.Ala145= Uncertain significance ★ same residue
ATF6 p.Ala145Glu Uncertain significance ★ ⚠ same residue
ATF6 p.Ala145Val Uncertain significance ★ ⚠ same residue
ATF6 c.1533+1G>C Pathogenic ★★ same type
ATF6 c.160-1G>A Likely pathogenic ★★ same type
ATF6 c.484+1G>A Likely pathogenic ★★ same type
ATF6 c.484+1G>T Likely pathogenic ★★ same type
ATF6 c.82+5G>T Pathogenic ★★ 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/atf6-p-ala145pro (accessed [today's date]).

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