Is ATF6 p.Arg508His (c.1523G>A) pathogenic?

ATF6 p.Arg508His (c.1523G>A) is classified Uncertain significance in ATF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.0994); Very rare (popmax 0.00936%, afr).

How common is ATF6 p.Arg508His (c.1523G>A) in the general population?

ATF6 p.Arg508His (c.1523G>A) is very rare (popmax 0.00936%, afr) (gnomAD).

What do computational predictors say about ATF6 p.Arg508His (c.1523G>A)?

AlphaMissense predicts likely benign (score 0.0994) — an in-silico prediction, not a clinical call.

ATF6 p.Arg508His

c.1523G>A · rs374129058 · VCV956523

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00936%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0994	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.87	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 0.31	GERP 0.077
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	23.5	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 0.00936% African / African-American · 7/74,816 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00273% 44/1,610,766 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00936%	10,688
Remaining individualsnot grpmax-eligible	0.00481%	20,779
South Asian	0.0044%	22,723
European (non-Finnish)	0.00238%	42,049
East Asian	0.00223%	44,818
Admixed American	0.00167%	59,960

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.Arg508His
Coding: c.1523G>A
MANE Select: NM_007348
dbSNP: rs374129058
Type: single nucleotide variant
Location: chr1:161853313 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 508: the 'interaction with thbs4' region

Full ATF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATF6 p.Arg508Cys Uncertain significance ★ ⚠ same residue
ATF6 c.1533+1G>C Pathogenic ★★ same type
ATF6 c.160-1G>A Likely pathogenic ★★ same type
ATF6 c.484+1G>A Likely pathogenic ★★ same type
ATF6 c.484+1G>T Likely pathogenic ★★ same type
ATF6 c.82+5G>T Pathogenic ★★ same type
ATF6 p.Arg324Cys Pathogenic ★★ same type
ATF6 p.Arg376Ter Pathogenic ★★ 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/atf6-p-arg508his (accessed [today's date]).

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