Is ATF6 p.Ser668Pro (c.2002T>C) pathogenic?

ATF6 p.Ser668Pro (c.2002T>C) is classified Uncertain significance in ATF6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-01-01). AlphaMissense: likely benign (0.1135); Absent from gnomAD v4.1; Associated with inherited retinal dystrophy.

What condition is associated with ATF6 p.Ser668Pro (c.2002T>C)?

ATF6 p.Ser668Pro (c.2002T>C) is associated with inherited retinal dystrophy (ClinVar).

How common is ATF6 p.Ser668Pro (c.2002T>C) in the general population?

ATF6 p.Ser668Pro (c.2002T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATF6 p.Ser668Pro (c.2002T>C)?

AlphaMissense predicts likely benign (score 0.1135) — an in-silico prediction, not a clinical call.

ATF6 p.Ser668Pro

c.2002T>C · VCV3250296

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1135 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1135	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -6.34	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 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	23.9	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

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.Ser668Pro
Coding: c.2002T>C
MANE Select: NM_007348
Type: single nucleotide variant
Location: chr1:161958643 (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

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ATF6 p.Asp109Gly Uncertain significance ★★ ⚠ same condition
ATF6 p.Asp26Gly Uncertain significance ★ ⚠ same condition
ATF6 p.Ala336Thr Uncertain significance ⚠ same condition
ATF6 p.Pro652Ala Uncertain significance ⚠ same condition
ATF6 p.Ile171fs Pathogenic ★ same condition
ATF6 p.His488_Val492del Likely pathogenic same condition
ATF6 p.Lys496fs Pathogenic same condition
ATF6 c.1533+1G>C 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-ser668pro (accessed [today's date]).

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