Is APC2 p.Pro1253Ser (c.3757C>T) pathogenic?

APC2 p.Pro1253Ser (c.3757C>T) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-29). AlphaMissense: likely benign (0.2891); Very rare (popmax 0.004%, afr); Associated with APC2-related disorder.

What condition is associated with APC2 p.Pro1253Ser (c.3757C>T)?

APC2 p.Pro1253Ser (c.3757C>T) is associated with APC2-related disorder (ClinVar).

How common is APC2 p.Pro1253Ser (c.3757C>T) in the general population?

APC2 p.Pro1253Ser (c.3757C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about APC2 p.Pro1253Ser (c.3757C>T)?

AlphaMissense predicts likely benign (score 0.2891) — an in-silico prediction, not a clinical call.

APC2 p.Pro1253Ser

c.3757C>T · rs756181897 · VCV1905443

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

APC2-related disorder

Computational evidence

Protein change
AlphaMissense	0.2891	likely benign
REVEL	0.678	pathogenic-leaning
SaProt	LLR -5.55	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.5, phastCons 1
Overall
CADD	23.9	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 0.004% African / African-American · 3/74,924 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000869% 14/1,611,694 alleles · very rare exomes 10/1,459,466 · genomes 4/152,228 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
Admixed American	0.00167%	59,964
Remaining individualsnot grpmax-eligible	0.0016%	62,402
European (non-Finnish)	0.000763%	131,078

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.Pro1253Ser
Coding: c.3757C>T
MANE Select: NM_005883
dbSNP: rs756181897
Type: single nucleotide variant
Location: chr19:1467058 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 1253: the '5 x 20 aa approximate repeat of f-x-v-e-x-t-p-x-c-f-s-r-x-s-s-l-s-s-l-s' region; the 'interaction with ctnnb1' region; a UniProt-annotated variant site (in cdcbm10)

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

Disease context

APC2-related disorder

Similar variants

APC2 p.Pro1253= Likely benign ★ same residue
APC2 p.Arg853Pro Uncertain significance ★★ ⚠ same condition
APC2 p.Gln1000Lys Uncertain significance ★★ ⚠ same condition
APC2 p.Pro2066Ala Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1602Trp Uncertain significance ★ ⚠ same condition
APC2 p.Leu283= Conflicting classifications of pathogenicity ★ same condition
APC2 p.Ser1861Asn Uncertain significance ★ ⚠ same condition
APC2 c.1638+1G>C Likely pathogenic same condition

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-pro1253ser (accessed [today's date]).

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