Is ATF6 p.Ser438Cys (c.1312A>T) pathogenic?

ATF6 p.Ser438Cys (c.1312A>T) is classified Uncertain significance in ATF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-12). AlphaMissense: likely benign (0.1066); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ATF6 p.Ser438Cys (c.1312A>T)?

ATF6 p.Ser438Cys (c.1312A>T) is associated with Inborn genetic diseases (ClinVar).

How common is ATF6 p.Ser438Cys (c.1312A>T) in the general population?

ATF6 p.Ser438Cys (c.1312A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATF6 p.Ser438Cys (c.1312A>T)?

AlphaMissense predicts likely benign (score 0.1066) — an in-silico prediction, not a clinical call.

ATF6 p.Ser438Cys

c.1312A>T · rs2525322524 · VCV2559479

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1066 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1066	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -10.21	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP -0.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	21.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ATF6
Protein: p.Ser438Cys
Coding: c.1312A>T
MANE Select: NM_007348
dbSNP: rs2525322524
Type: single nucleotide variant
Location: chr1:161846573 (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

Disease context

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

Similar variants

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
ATF6 p.Arg642Thr 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-ser438cys (accessed [today's date]).

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