Is APC2 p.Pro253Ser (c.757C>T) pathogenic?

APC2 p.Pro253Ser (c.757C>T) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.0769); Absent from gnomAD v4.1; Associated with intellectual developmental disorder, autosomal recessive 74.

What condition is associated with APC2 p.Pro253Ser (c.757C>T)?

APC2 p.Pro253Ser (c.757C>T) is associated with intellectual developmental disorder, autosomal recessive 74 (ClinVar).

How common is APC2 p.Pro253Ser (c.757C>T) in the general population?

APC2 p.Pro253Ser (c.757C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APC2 p.Pro253Ser (c.757C>T)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

APC2 p.Pro253Ser

c.757C>T · rs555858661 · VCV1033037

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder, autosomal recessive 74

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -6.11	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 0.94	GERP 1.2, phastCons 0.001
Overall
CADD	12.04	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APC2
Protein: p.Pro253Ser
Coding: c.757C>T
MANE Select: NM_005883
dbSNP: rs555858661
Type: single nucleotide variant
Location: chr19:1456345 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 253: the 'disordered' region; a UniProt-annotated variant site (in cdcbm10)

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

Disease context

intellectual developmental disorder, autosomal recessive 74 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APC2 p.Pro253Thr Uncertain significance ★ ⚠ same residue
APC2 p.Ala1703Glu Uncertain significance ★★ ⚠ same condition
APC2 p.Ala791Val Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1539Pro Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1708Leu Uncertain significance ★★ ⚠ same condition
APC2 p.Gly1007Ser Uncertain significance ★★ ⚠ same condition
APC2 p.Gly1958Arg Uncertain significance ★★ ⚠ same condition
APC2 p.Pro1327Ser Uncertain significance ★★ ⚠ 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-pro253ser (accessed [today's date]).

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