Is APCDD1L p.Thr299Pro (c.895A>C) pathogenic?

APCDD1L p.Thr299Pro (c.895A>C) is classified Uncertain significance in APCDD1L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: ambiguous (0.4615); Ultra-rare (popmax 0.0527%, amr).

How common is APCDD1L p.Thr299Pro (c.895A>C) in the general population?

APCDD1L p.Thr299Pro (c.895A>C) is ultra-rare (popmax 0.0527%, amr) (gnomAD).

What do computational predictors say about APCDD1L p.Thr299Pro (c.895A>C)?

AlphaMissense predicts ambiguous (score 0.4615) — an in-silico prediction, not a clinical call.

APCDD1L p.Thr299Pro

c.895A>C · VCV4122895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4615 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0527%, amr)

Computational evidence

Protein change
AlphaMissense	0.4615	ambiguous
REVEL	0.489	indeterminate
SaProt	LLR -16.27	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 54 kb · p 0.77 · regional, not allelic
Overall
CADD	23.4	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 0.0527% Admixed American · 29/55,068 alleles

Filtering AF 0.0376% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0326%

Overall 0.00225% 35/1,553,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0527%	1,899
Remaining individualsnot grpmax-eligible	0.01%	9,956

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: APCDD1L
Protein: p.Thr299Pro
Coding: c.895A>C
MANE Select: NM_153360
Type: single nucleotide variant
Location: chr20:58461401 (GRCh38)
Gene constraint: LOEUF 1.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.31

Full APCDD1L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APCDD1L p.Thr299Ile Uncertain significance ★ ⚠ same residue
APCDD1L p.Ala141Val Uncertain significance ★ ⚠ same type
APCDD1L p.Ala159Glu Uncertain significance ★ ⚠ same type
APCDD1L p.Ala246Ser Uncertain significance ★ ⚠ same type
APCDD1L p.Ala333Thr Uncertain significance ★ ⚠ same type
APCDD1L p.Ala3Ser Uncertain significance ★ ⚠ same type
APCDD1L p.Arg139His Uncertain significance ★ ⚠ same type
APCDD1L p.Arg139Pro 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/apcdd1l-p-thr299pro (accessed [today's date]).

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