Is APCDD1 p.Pro252Ala (c.754C>G) pathogenic?

APCDD1 p.Pro252Ala (c.754C>G) is classified Uncertain significance in APCDD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0735); Ultra-rare (popmax 0.066%, mid).

How common is APCDD1 p.Pro252Ala (c.754C>G) in the general population?

APCDD1 p.Pro252Ala (c.754C>G) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about APCDD1 p.Pro252Ala (c.754C>G)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

APCDD1 p.Pro252Ala

c.754C>G · rs549800578 · VCV2532994

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -3.93	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 4.8	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 33 kb · p 0.062 · regional, not allelic
Overall
CADD	17.98	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 0.066% Middle Eastern · 4/6,060 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00273% 44/1,613,512 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,515
Admixed American	0.01%	10,001
South Asian	0.00768%	13,013
Remaining individualsnot grpmax-eligible	0.0048%	20,827
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00186%	53,638
African / African-American	0.00133%	74,914

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: APCDD1
Protein: p.Pro252Ala
Coding: c.754C>G
MANE Select: NM_153000
dbSNP: rs549800578
Type: single nucleotide variant
Location: chr18:10472041 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI 0.59 (gnomAD)
Structure: AlphaFold pLDDT 82.10

Full APCDD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APCDD1 p.Pro252Thr Uncertain significance ★ ⚠ same residue
APCDD1 p.Ala176Thr Uncertain significance ★★ ⚠ same type
APCDD1 p.Ala343Thr Uncertain significance ★★ ⚠ same type
APCDD1 p.Arg169His Uncertain significance ★★ ⚠ same type
APCDD1 p.Arg213Gln Uncertain significance ★★ ⚠ same type
APCDD1 p.Arg303Cys Uncertain significance ★★ ⚠ same type
APCDD1 p.Arg344Trp Uncertain significance ★★ ⚠ same type
APCDD1 p.Arg432Gln 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/apcdd1-p-pro252ala (accessed [today's date]).

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