Is ATF6B p.Val451Ile (c.1351G>A) pathogenic?

ATF6B p.Val451Ile (c.1351G>A) is classified Uncertain significance in ATF6B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely benign (0.0755); Very rare (popmax 0.00669%, eas).

How common is ATF6B p.Val451Ile (c.1351G>A) in the general population?

ATF6B p.Val451Ile (c.1351G>A) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about ATF6B p.Val451Ile (c.1351G>A)?

AlphaMissense predicts likely benign (score 0.0755) — an in-silico prediction, not a clinical call.

ATF6B p.Val451Ile

c.1351G>A · rs1185572692 · VCV2229846

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0755	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -7.61	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 0.043	GERP -1.9
Overall
CADD	6.98	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 0.00669% East Asian · 3/44,864 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000274% 4/1,458,386 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,955
European (non-Finnish)	8.49e-05%	1,178,396

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.Val451Ile
Coding: c.1351G>A
MANE Select: NM_004381
dbSNP: rs1185572692
Type: single nucleotide variant
Location: chr6:32117932 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.31
Residue 451: the 'disordered' 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-val451ile (accessed [today's date]).

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