Is APCDD1 p.Ser495Cys (c.1484C>G) pathogenic?

APCDD1 p.Ser495Cys (c.1484C>G) is classified Uncertain significance in APCDD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely benign (0.0833); Ultra-rare (popmax 0.0195%, nfe).

How common is APCDD1 p.Ser495Cys (c.1484C>G) in the general population?

APCDD1 p.Ser495Cys (c.1484C>G) is ultra-rare (popmax 0.0195%, nfe) (gnomAD).

What do computational predictors say about APCDD1 p.Ser495Cys (c.1484C>G)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

APCDD1 p.Ser495Cys

c.1484C>G · rs138401718 · VCV2347251

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0195%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -8.34	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 1.4	GERP 0.74, phastCons 0.001
Regional constraint	o/e 0.93	unconstrained · MANE · 33 kb · p 0.062 · regional, not allelic
Overall
CADD	14.08	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 0.0195% European (non-Finnish) · 230/1,180,036 alleles

Filtering AF 0.0174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.0148% 239/1,613,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0195%	5,131
Remaining individualsnot grpmax-eligible	0.0096%	10,413
Finnishnot grpmax-eligible	0.00314%	31,892
African / African-American	0.00133%	74,944

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.Ser495Cys
Coding: c.1484C>G
MANE Select: NM_153000
dbSNP: rs138401718
Type: single nucleotide variant
Location: chr18:10487977 (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.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
APCDD1 p.Glu393Lys 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-ser495cys (accessed [today's date]).

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