Is ATF6 p.Pro652Ser (c.1954C>T) pathogenic?

ATF6 p.Pro652Ser (c.1954C>T) is classified Uncertain significance in ATF6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-12). AlphaMissense: likely benign (0.0654); Ultra-rare (popmax 0.0233%, amr); Associated with Inborn genetic diseases.

What condition is associated with ATF6 p.Pro652Ser (c.1954C>T)?

ATF6 p.Pro652Ser (c.1954C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ATF6 p.Pro652Ser (c.1954C>T) in the general population?

ATF6 p.Pro652Ser (c.1954C>T) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about ATF6 p.Pro652Ser (c.1954C>T)?

AlphaMissense predicts likely benign (score 0.0654) — an in-silico prediction, not a clinical call.

ATF6 p.Pro652Ser

c.1954C>T · rs757919002 · VCV837666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0654 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0654	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -5.36	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	15.83	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 0.0233% Admixed American · 14/59,996 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00731% 118/1,613,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,285
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00797%	12,553
Finnishnot grpmax-eligible	0.00312%	32,011
African / African-American	0.00134%	74,862
South Asian	0.0011%	91,050

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.Pro652Ser
Coding: c.1954C>T
MANE Select: NM_007348
dbSNP: rs757919002
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

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

Similar variants

ATF6 p.Pro652Ala Uncertain significance ⚠ same residue
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

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-pro652ser (accessed [today's date]).

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