Is APC2 p.Phe140Ser (c.419T>C) pathogenic?

APC2 p.Phe140Ser (c.419T>C) is classified Likely benign in APC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-15). AlphaMissense: likely pathogenic (0.5827); Rare (popmax 0.342%, nfe).

How common is APC2 p.Phe140Ser (c.419T>C) in the general population?

APC2 p.Phe140Ser (c.419T>C) is rare (popmax 0.342%, nfe) (gnomAD).

What do computational predictors say about APC2 p.Phe140Ser (c.419T>C)?

AlphaMissense predicts likely pathogenic (score 0.5827) — an in-silico prediction, not a clinical call.

APC2 p.Phe140Ser

c.419T>C · rs143295265 · VCV713027

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.5827 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.342%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5827	likely pathogenic
REVEL	0.414	indeterminate
SaProt	LLR -3.85	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.2, phastCons 1
Overall
CADD	24.3	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 0.342% European (non-Finnish) · 3,995/1,168,844 alleles

Filtering AF 0.333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.329%

Overall 0.274% 4,318/1,574,352 alleles · rare exomes 4,063/1,422,074 · genomes 255/152,278 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.342%	293
Remaining individualsnot grpmax-eligible	0.222%	451
Middle Eastern	0.122%	819
Admixed American	0.111%	903
African / African-American	0.0843%	1,187
South Asian	0.0688%	1,454
Finnishnot grpmax-eligible	0.00961%	10,402
Ashkenazi Jewishnot grpmax-eligible	0.00714%	14,013

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: APC2
Protein: p.Phe140Ser
Coding: c.419T>C
MANE Select: NM_005883
dbSNP: rs143295265
Type: single nucleotide variant
Location: chr19:1455154 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87

Full APC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APC2 p.Ala1059Glu Uncertain significance ★★ ⚠ same type
APC2 p.Ala1103Thr Uncertain significance ★★ ⚠ same type
APC2 p.Ala1116Val Uncertain significance ★★ ⚠ same type
APC2 p.Ala126Ser Uncertain significance ★★ ⚠ same type
APC2 p.Ala1311Thr Uncertain significance ★★ ⚠ same type
APC2 p.Ala1359Val Uncertain significance ★★ ⚠ same type
APC2 p.Ala1438Thr Uncertain significance ★★ ⚠ same type
APC2 p.Ala1492Glu Uncertain significance ★★ ⚠ 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/apc2-p-phe140ser (accessed [today's date]).

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