Is DPEP3 p.Arg166Cys (c.496C>T) pathogenic?

DPEP3 p.Arg166Cys (c.496C>T) is classified Uncertain significance in DPEP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.1845); Ultra-rare (popmax 0.0267%, amr).

How common is DPEP3 p.Arg166Cys (c.496C>T) in the general population?

DPEP3 p.Arg166Cys (c.496C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about DPEP3 p.Arg166Cys (c.496C>T)?

AlphaMissense predicts likely benign (score 0.1845) — an in-silico prediction, not a clinical call.

DPEP3 p.Arg166Cys

c.496C>T · rs183104878 · VCV2359867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1845 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1845	likely benign
REVEL	0.325	indeterminate
SaProt	LLR -14.28	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,612 bp · p 0.0029 · regional, not allelic
Overall
CADD	25.8	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 0.0267% Admixed American · 16/60,014 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00217% 35/1,614,082 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,751
South Asian	0.00439%	22,769
Remaining individualsnot grpmax-eligible	0.0016%	62,496
African / African-American	0.00133%	75,030
European (non-Finnish)	0.0011%	90,769

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: DPEP3
Protein: p.Arg166Cys
Coding: c.496C>T
MANE Select: NM_001370198
dbSNP: rs183104878
Type: single nucleotide variant
Location: chr16:67978545 (GRCh38)
Gene constraint: LOEUF 1.097 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.15 · 2 PDB
Residue 166: an α-helix; a disulfide bond

Full DPEP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DPEP3 c.-44A>T Uncertain significance ★ same type
DPEP3 c.-47C>G Uncertain significance ★ same type
DPEP3 c.-5G>T Uncertain significance ★ same type
DPEP3 c.-62C>T Uncertain significance ★ same type
DPEP3 c.-6C>T Uncertain significance ★ same type
DPEP3 p.Ala11Thr Uncertain significance ★ ⚠ same type
DPEP3 p.Ala157Pro Uncertain significance ★ ⚠ same type
DPEP3 p.Ala284Gly 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/dpep3-p-arg166cys (accessed [today's date]).

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