Is ATF6 p.Ser16Ter (c.45dup) pathogenic?

ATF6 p.Ser16Ter (c.45dup) is classified Pathogenic in ATF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-08). Very rare (popmax 0.00267%, afr).

How common is ATF6 p.Ser16Ter (c.45dup) in the general population?

ATF6 p.Ser16Ter (c.45dup) is very rare (popmax 0.00267%, afr) (gnomAD).

ATF6 p.Ser16Ter

c.45dup · rs1379407031 · VCV1951902

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.4	GERP 3, phastCons 0.24
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,914 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,478 alleles · very rare

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.Ser16Ter
Coding: c.45dup
MANE Select: NM_007348
dbSNP: rs1379407031
Type: Duplication
Location: chr1:161766401 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 16: the 'transcription activation' region

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

Similar variants

ATF6 p.Ser16Ile Benign/Likely benign ★★ same residue
ATF6 p.Ile534fs Likely pathogenic ★ same type
ATF6 p.Pro266_Asn267insTer Pathogenic ★ same type
ATF6 p.Val371fs Pathogenic ★ same type
ATF6 p.Met591fs Uncertain significance ★ same type
ATF6 c.485-7dup Benign ★ same type
ATF6 c.355_356dupG Pathogenic same type
ATF6 p.Asn140Ter Likely 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-ser16ter (accessed [today's date]).

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