Is ATF6 p.Pro157Ser (c.469C>T) pathogenic?

ATF6 p.Pro157Ser (c.469C>T) is classified Benign in ATF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0751); Common (popmax 38.8%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ATF6 p.Pro157Ser (c.469C>T)?

AlphaMissense predicts likely benign (score 0.0751) — an in-silico prediction, not a clinical call.

ATF6 p.Pro157Ser

Q: How common is ATF6 p.Pro157Ser (c.469C>T) in the general population?

ATF6 p.Pro157Ser (c.469C>T) is common (popmax 38.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.469C>T · rs1135983 · VCV1164407

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0751 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 38.8%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0751	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -5.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.96	GERP 0.21, phastCons 0.57
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	15.14	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 38.8% Admixed American · 23,044/59,382 alleles

Filtering AF 38.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 38.2%

Overall 9.39% 151,013/1,607,720 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	38.8%	3
East Asian	33.8%	3
African / African-American	13.4%	7
Ashkenazi Jewishnot grpmax-eligible	10.4%	10
Remaining individualsnot grpmax-eligible	10.3%	10
Middle Eastern	9.58%	10
South Asian	8.6%	12
European (non-Finnish)	6.87%	15
Finnishnot grpmax-eligible	6.57%	15
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.Pro157Ser
Coding: c.469C>T
MANE Select: NM_007348
dbSNP: rs1135983
Type: single nucleotide variant
Location: chr1:161791522 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 157: a UniProt-annotated variant site (in); the 'disordered' region

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

Similar variants

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
ATF6 p.Arg324Cys Pathogenic ★★ same type
ATF6 p.Arg376Ter Pathogenic ★★ same type
ATF6 p.Gln237Ter 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-pro157ser (accessed [today's date]).

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