Is ATF6 p.Arg560His (c.1679G>A) pathogenic?

ATF6 p.Arg560His (c.1679G>A) is classified Conflicting classifications of pathogenicity in ATF6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.073); Ultra-rare (popmax 0.0134%, afr).

How common is ATF6 p.Arg560His (c.1679G>A) in the general population?

ATF6 p.Arg560His (c.1679G>A) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about ATF6 p.Arg560His (c.1679G>A)?

AlphaMissense predicts likely benign (score 0.073) — an in-silico prediction, not a clinical call.

ATF6 p.Arg560His

c.1679G>A · rs375366825 · VCV958172

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.073 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.073	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -4.91	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 1.2	GERP -0.85, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	17.59	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 0.0134% African / African-American · 10/74,872 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00118% 19/1,612,506 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,487
East Asian	0.00446%	22,412
Remaining individualsnot grpmax-eligible	0.0016%	62,408
South Asian	0.0011%	91,010
European (non-Finnish)	0.000424%	235,766

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.Arg560His
Coding: c.1679G>A
MANE Select: NM_007348
dbSNP: rs375366825
Type: single nucleotide variant
Location: chr1:161863272 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 560: the 'interaction with thbs4' region

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

Similar variants

ATF6 p.Arg560Cys Uncertain significance ★ same residue
ATF6 p.Arg560Ser 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

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-arg560his (accessed [today's date]).

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