Is APC2 p.Pro1327Ser (c.3979C>T) pathogenic?

APC2 p.Pro1327Ser (c.3979C>T) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-12). AlphaMissense: likely benign (0.0826); Rare (popmax 0.355%, afr); Associated with Inborn genetic diseases.

How common is APC2 p.Pro1327Ser (c.3979C>T) in the general population?

APC2 p.Pro1327Ser (c.3979C>T) is rare (popmax 0.355%, afr) (gnomAD).

What do computational predictors say about APC2 p.Pro1327Ser (c.3979C>T)?

AlphaMissense predicts likely benign (score 0.0826) — an in-silico prediction, not a clinical call.

APC2 p.Pro1327Ser

Q: What condition is associated with APC2 p.Pro1327Ser (c.3979C>T)?

APC2 p.Pro1327Ser (c.3979C>T) is associated with Inborn genetic diseases, intellectual developmental disorder, autosomal recessive 74, cortical dysplasia, complex, with other brain malformations 10 (ClinVar).

c.3979C>T · rs535779056 · VCV978190

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0826 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.355%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0826	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -6.86	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 -0.33	GERP -2.8
Overall
CADD	2.075	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

Grpmax group 0.355% African / African-American · 230/64,866 alleles

Filtering AF 0.317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.302%

Overall 0.018% 237/1,314,972 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.355%	282
Admixed American	0.0124%	8,055
Remaining individualsnot grpmax-eligible	0.00401%	24,912
East Asian	0.00312%	32,022
European (non-Finnish)	9.64e-05%	1,036,994

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.Pro1327Ser
Coding: c.3979C>T
MANE Select: NM_005883
dbSNP: rs535779056
Type: single nucleotide variant
Location: chr19:1467280 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 1327: 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; 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual developmental disorder, autosomal recessive 74 cortical dysplasia, complex, with other brain malformations 10

Similar variants

APC2 p.Ala1059Glu Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1103Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1116Val Uncertain significance ★★ ⚠ same condition
APC2 p.Ala126Ser Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1311Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1359Val Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1438Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1492Glu 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-pro1327ser (accessed [today's date]).

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