Is ATF6 p.Phe421Ser (c.1262T>C) pathogenic?

ATF6 p.Phe421Ser (c.1262T>C) is classified Uncertain significance in ATF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-14). AlphaMissense: likely pathogenic (0.855); Absent from gnomAD v4.1.

How common is ATF6 p.Phe421Ser (c.1262T>C) in the general population?

ATF6 p.Phe421Ser (c.1262T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATF6 p.Phe421Ser (c.1262T>C)?

AlphaMissense predicts likely pathogenic (score 0.855) — an in-silico prediction, not a clinical call.

ATF6 p.Phe421Ser

c.1262T>C · rs1049343696 · VCV1464144

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.855 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.855	likely pathogenic
REVEL	0.268	benign-leaning
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	25.2	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.Phe421Ser
Coding: c.1262T>C
MANE Select: NM_007348
dbSNP: rs1049343696
Type: single nucleotide variant
Location: chr1:161846523 (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 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-phe421ser (accessed [today's date]).

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