Is APCDD1L p.Arg139Pro (c.416G>C) pathogenic?

APCDD1L p.Arg139Pro (c.416G>C) is classified Uncertain significance in APCDD1L (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). AlphaMissense: likely benign (0.0974); Very rare (popmax 0.00238%, eas).

How common is APCDD1L p.Arg139Pro (c.416G>C) in the general population?

APCDD1L p.Arg139Pro (c.416G>C) is very rare (popmax 0.00238%, eas) (gnomAD).

What do computational predictors say about APCDD1L p.Arg139Pro (c.416G>C)?

AlphaMissense predicts likely benign (score 0.0974) — an in-silico prediction, not a clinical call.

APCDD1L p.Arg139Pro

c.416G>C · rs1274389051 · VCV3127788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00238%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0974	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.91	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 -1.5	GERP -4.5
Regional constraint	o/e 0.99	unconstrained · MANE · 54 kb · p 0.77 · regional, not allelic
Overall
CADD	13.96	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 0.00238% East Asian · 1/41,952 alleles

Overall 0.000141% 2/1,418,740 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00238%	41,952
African / African-American	0.00136%	73,366

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.Arg139Pro
Coding: c.416G>C
MANE Select: NM_153360
dbSNP: rs1274389051
Type: single nucleotide variant
Location: chr20:58467431 (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.Arg139His 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.Arg153Cys Uncertain significance ★ ⚠ same type
APCDD1L p.Arg166Trp 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-arg139pro (accessed [today's date]).

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