Is APCDD1 p.Ser444Arg (c.1332C>A) pathogenic?

APCDD1 p.Ser444Arg (c.1332C>A) is classified Likely benign in APCDD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-06). AlphaMissense: likely pathogenic (0.9968); Ultra-rare (popmax 0.0994%, nfe).

How common is APCDD1 p.Ser444Arg (c.1332C>A) in the general population?

APCDD1 p.Ser444Arg (c.1332C>A) is ultra-rare (popmax 0.0994%, nfe) (gnomAD).

What do computational predictors say about APCDD1 p.Ser444Arg (c.1332C>A)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

APCDD1 p.Ser444Arg

c.1332C>A · rs200082076 · VCV2075453

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0994%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic · top 4% in APCDD1
REVEL	0.302	indeterminate
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.4	GERP -3.9
Regional constraint	o/e 0.93	unconstrained · MANE · 33 kb · p 0.062 · regional, not allelic
Overall
CADD	13.02	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 0.0994% European (non-Finnish) · 1,173/1,180,054 alleles

Filtering AF 0.0946% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0927%

Overall 0.0788% 1,271/1,613,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0994%	1,006
Remaining individualsnot grpmax-eligible	0.0544%	1,838
Finnishnot grpmax-eligible	0.0454%	2,201
Admixed American	0.035%	2,857
African / African-American	0.0147%	6,811
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,801
South Asian	0.0011%	91,088

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.Ser444Arg
Coding: c.1332C>A
MANE Select: NM_153000
dbSNP: rs200082076
Type: single nucleotide variant
Location: chr18:10487825 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI 0.59 (gnomAD)
Structure: AlphaFold pLDDT 82.10
Residue 444: the 'disordered' region

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-ser444arg (accessed [today's date]).

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