Is DPEP2 p.Leu85Pro (c.254T>C) pathogenic?

DPEP2 p.Leu85Pro (c.254T>C) is classified Uncertain significance in DPEP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-07). AlphaMissense: ambiguous (0.5296); Rare (popmax 0.136%, afr).

How common is DPEP2 p.Leu85Pro (c.254T>C) in the general population?

DPEP2 p.Leu85Pro (c.254T>C) is rare (popmax 0.136%, afr) (gnomAD).

What do computational predictors say about DPEP2 p.Leu85Pro (c.254T>C)?

AlphaMissense predicts ambiguous (score 0.5296) — an in-silico prediction, not a clinical call.

DPEP2 p.Leu85Pro

c.254T>C · VCV3504833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5296 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, afr)

Computational evidence

Protein change
AlphaMissense	0.5296	ambiguous
REVEL	0.357	indeterminate
SaProt	LLR -12.44	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,703 bp · p 0.27 · regional, not allelic
Overall
CADD	24.5	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 0.136% African / African-American · 102/74,998 alleles

Filtering AF 0.115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.107%

Overall 0.00695% 112/1,611,128 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.136%	735
Remaining individualsnot grpmax-eligible	0.00962%	10,397
South Asian	0.0033%	30,261
Admixed American	0.00167%	59,858

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: DPEP2
Protein: p.Leu85Pro
Coding: c.254T>C
MANE Select: NM_022355
Type: single nucleotide variant
Location: chr16:67992959 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.94

Full DPEP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DPEP2 p.Leu85His Uncertain significance ★ ⚠ same residue
DPEP2 p.Ala226Thr Uncertain significance ★ ⚠ same type
DPEP2 p.Ala276Thr Uncertain significance ★ ⚠ same type
DPEP2 p.Ala33Thr Uncertain significance ★ ⚠ same type
DPEP2 p.Ala59Thr Uncertain significance ★ ⚠ same type
DPEP2 p.Ala78Val Uncertain significance ★ ⚠ same type
DPEP2 p.Arg147Cys Uncertain significance ★ ⚠ same type
DPEP2 p.Arg147His 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/dpep2-p-leu85pro (accessed [today's date]).

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