Is ATF6B p.Pro52Ser (c.154C>T) pathogenic?

ATF6B p.Pro52Ser (c.154C>T) is classified Uncertain significance in ATF6B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: likely benign (0.082); Rare (popmax 0.285%, afr).

How common is ATF6B p.Pro52Ser (c.154C>T) in the general population?

ATF6B p.Pro52Ser (c.154C>T) is rare (popmax 0.285%, afr) (gnomAD).

What do computational predictors say about ATF6B p.Pro52Ser (c.154C>T)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

ATF6B p.Pro52Ser

c.154C>T · rs17201623 · VCV2367251

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.285%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.02	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 5	GERP 0.75, phastCons 1
Overall
CADD	18.06	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 0.285% African / African-American · 214/75,046 alleles

Filtering AF 0.254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.242%

Overall 0.139% 2,247/1,614,190 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.285%	351
Remaining individualsnot grpmax-eligible	0.162%	619
European (non-Finnish)	0.157%	636
Middle Eastern	0.066%	1,516
Admixed American	0.0483%	2,070
Finnishnot grpmax-eligible	0.0312%	3,202
South Asian	0.0263%	3,795
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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: ATF6B
Protein: p.Pro52Ser
Coding: c.154C>T
MANE Select: NM_004381
dbSNP: rs17201623
Type: single nucleotide variant
Location: chr6:32127688 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.31
Residue 52: the 'transcription activation' region

Full ATF6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATF6B p.His601Leu Likely benign ★★ same type
ATF6B p.Ala11Thr Uncertain significance ★ ⚠ same type
ATF6B p.Ala236Asp Uncertain significance ★ ⚠ same type
ATF6B p.Ala2Thr Uncertain significance ★ ⚠ same type
ATF6B p.Ala2Val Uncertain significance ★ ⚠ same type
ATF6B p.Ala422Val Uncertain significance ★ ⚠ same type
ATF6B p.Ala686Glu Uncertain significance ★ ⚠ same type
ATF6B p.Ala686Val Uncertain significance ★ ⚠ 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/atf6b-p-pro52ser (accessed [today's date]).

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