Is ANAPC1 p.Ser46= (c.138T>A) pathogenic?

ANAPC1 p.Ser46= (c.138T>A) is classified Likely benign in ANAPC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-06). Ultra-rare (popmax 0.0373%, afr).

How common is ANAPC1 p.Ser46= (c.138T>A) in the general population?

ANAPC1 p.Ser46= (c.138T>A) is ultra-rare (popmax 0.0373%, afr) (gnomAD).

ANAPC1 p.Ser46=

c.138T>A · rs537608338 · VCV757630

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP 0.53, phastCons 0.62
Overall
CADD	7.182	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0373% African / African-American · 28/75,038 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.00725% 117/1,613,570 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.101%	986
African / African-Americangrpmax	0.0373%	2,680
South Asian	0.022%	4,552
Remaining individualsnot grpmax-eligible	0.0128%	7,809
Admixed American	0.00833%	12,000
East Asian	0.00223%	44,880
European (non-Finnish)	0.00212%	47,189

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ANAPC1
Protein: p.Ser46=
Coding: c.138T>A
MANE Select: NM_022662
dbSNP: rs537608338
Type: single nucleotide variant
Location: chr2:111880688 (GRCh38)
Gene constraint: LOEUF 0.273 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.46 · 21 PDB
Residue 46: an α-helix

Full ANAPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANAPC1 p.Gly79Glu Uncertain significance ★★ ⚠ same type
ANAPC1 p.Leu1274Phe Uncertain significance ★★ ⚠ same type
ANAPC1 p.Trp1643Arg Uncertain significance ★★ ⚠ same type
ANAPC1 p.Tyr571Ser Uncertain significance ★★ ⚠ same type
ANAPC1 c.1651-23A>G Benign ★★ same type
ANAPC1 c.2704+11G>A Likely benign ★★ same type
ANAPC1 c.2742-3T>C Likely benign ★★ same type
ANAPC1 c.2742-7C>T Benign/Likely benign ★★ 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/anapc1-p-ser46 (accessed [today's date]).

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