Is ATF6 p.Ser280Arg (c.840C>G) pathogenic?

ATF6 p.Ser280Arg (c.840C>G) is classified Uncertain significance in ATF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-28). AlphaMissense: likely benign (0.2768); Very rare (popmax 0.00133%, afr).

How common is ATF6 p.Ser280Arg (c.840C>G) in the general population?

ATF6 p.Ser280Arg (c.840C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ATF6 p.Ser280Arg (c.840C>G)?

AlphaMissense predicts likely benign (score 0.2768) — an in-silico prediction, not a clinical call.

ATF6 p.Ser280Arg

c.840C>G · rs534635340 · VCV1382765

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2768	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -7.02	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 0.83	GERP 0.94, phastCons 0.48
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	15.32	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 0.00133% African / African-American · 1/75,022 alleles

Overall 6.84e-05% 1/1,461,768 alleles · very rare

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.Ser280Arg
Coding: c.840C>G
MANE Select: NM_007348
dbSNP: rs534635340
Type: single nucleotide variant
Location: chr1:161802203 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 56.09

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

Similar variants

ATF6 p.Ser280= Likely benign ★ 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
ATF6 p.Arg324Cys Pathogenic ★★ same type
ATF6 p.Arg376Ter 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-ser280arg (accessed [today's date]).

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