Is ATF6 p.Phe20Ser (c.59T>C) pathogenic?

ATF6 p.Phe20Ser (c.59T>C) is classified Benign in ATF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0513); Low-frequency (popmax 2.29%, mid).

How common is ATF6 p.Phe20Ser (c.59T>C) in the general population?

ATF6 p.Phe20Ser (c.59T>C) is low-frequency (popmax 2.29%, mid) (gnomAD).

What do computational predictors say about ATF6 p.Phe20Ser (c.59T>C)?

AlphaMissense predicts likely benign (score 0.0513) — an in-silico prediction, not a clinical call.

ATF6 p.Phe20Ser

c.59T>C · rs35284289 · VCV1170814

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0513 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.29%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0513	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.28	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 -0.019	GERP -1.5
Regional constraint	o/e 0.93	unconstrained · MANE · 192 kb · p 0.056 · regional, not allelic
Overall
CADD	14.87	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 2.29% Middle Eastern · 139/6,058 alleles

Filtering AF 1.98% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.87%

Overall 1.57% 25,263/1,613,306 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.29%	44
South Asian	1.88%	53
European (non-Finnish)	1.83%	55
Remaining individualsnot grpmax-eligible	1.45%	69
Amishnot grpmax-eligible	0.987%	101
Admixed American	0.6%	167
Ashkenazi Jewishnot grpmax-eligible	0.48%	208
Finnishnot grpmax-eligible	0.336%	298
African / African-American	0.243%	412
East Asian	0.00669%	14,955

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.Phe20Ser
Coding: c.59T>C
MANE Select: NM_007348
dbSNP: rs35284289
Type: single nucleotide variant
Location: chr1:161766419 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 20: the 'transcription activation' region

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

Similar variants

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
ATF6 p.Gln237Ter 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-phe20ser (accessed [today's date]).

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