Is ATF6B p.Pro466Leu (c.1397C>T) pathogenic?

ATF6B p.Pro466Leu (c.1397C>T) is classified Likely benign in ATF6B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely benign (0.0666); Very rare (popmax 0.00372%, amr).

How common is ATF6B p.Pro466Leu (c.1397C>T) in the general population?

ATF6B p.Pro466Leu (c.1397C>T) is very rare (popmax 0.00372%, amr) (gnomAD).

What do computational predictors say about ATF6B p.Pro466Leu (c.1397C>T)?

AlphaMissense predicts likely benign (score 0.0666) — an in-silico prediction, not a clinical call.

ATF6B p.Pro466Leu

c.1397C>T · rs773465509 · VCV2269883

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00372%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0666	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -7.01	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 2.5	GERP -0.44, phastCons 1
Overall
CADD	14.56	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

Grpmax group 0.00372% Admixed American · 2/53,782 alleles

Filtering AF 0.000617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000231%

Overall 0.000211% 3/1,423,220 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00372%	26,891
European (non-Finnish)	8.59e-05%	1,163,894

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.Pro466Leu
Coding: c.1397C>T
MANE Select: NM_004381
dbSNP: rs773465509
Type: single nucleotide variant
Location: chr6:32117886 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.31
Residue 466: the 'disordered' region

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

Similar variants

ATF6B p.Pro466Arg Uncertain significance ★ ⚠ same residue
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

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-pro466leu (accessed [today's date]).

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