Is ATF6 p.Pro652Ala (c.1954C>G) pathogenic?

ATF6 p.Pro652Ala (c.1954C>G) is classified Uncertain significance in ATF6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-01-01). AlphaMissense: likely benign (0.0621); Very rare (popmax 0.000169%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with ATF6 p.Pro652Ala (c.1954C>G)?

ATF6 p.Pro652Ala (c.1954C>G) is associated with inherited retinal dystrophy (ClinVar).

How common is ATF6 p.Pro652Ala (c.1954C>G) in the general population?

ATF6 p.Pro652Ala (c.1954C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ATF6 p.Pro652Ala (c.1954C>G)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

ATF6 p.Pro652Ala

c.1954C>G · VCV3248830

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -6.09	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 2.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	16.6	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 0.000169% European (non-Finnish) · 2/1,179,974 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,840 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.Pro652Ala
Coding: c.1954C>G
MANE Select: NM_007348
Type: single nucleotide variant
Location: chr1:161958595 (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.Pro652Ser Uncertain significance ★★ ⚠ same residue
ATF6 p.Asp109Gly Uncertain significance ★★ ⚠ same condition
ATF6 p.Asp26Gly Uncertain significance ★ ⚠ same condition
ATF6 p.Ala336Thr Uncertain significance ⚠ same condition
ATF6 p.Ser668Pro Uncertain significance ⚠ same condition
ATF6 p.Ile171fs Pathogenic ★ same condition
ATF6 p.His488_Val492del Likely pathogenic same condition
ATF6 p.Lys496fs Pathogenic 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-pro652ala (accessed [today's date]).

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