Is DNPEP p.Ile245Thr (c.734T>C) pathogenic?

DNPEP p.Ile245Thr (c.734T>C) is classified Uncertain significance in DNPEP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: ambiguous (0.4462); Ultra-rare (popmax 0.0224%, eas).

How common is DNPEP p.Ile245Thr (c.734T>C) in the general population?

DNPEP p.Ile245Thr (c.734T>C) is ultra-rare (popmax 0.0224%, eas) (gnomAD).

What do computational predictors say about DNPEP p.Ile245Thr (c.734T>C)?

AlphaMissense predicts ambiguous (score 0.4462) — an in-silico prediction, not a clinical call.

DNPEP p.Ile245Thr

c.734T>C · rs549968429 · VCV2526156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4462 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0224%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4462	ambiguous
REVEL	0.95	strongly pathogenic-leaning
SaProt	LLR -13.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.2 · regional, not allelic
Overall
CADD	26.5	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 0.0224% East Asian · 10/44,682 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00977%

Overall 0.00174% 28/1,610,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0224%	4,468
South Asian	0.0187%	5,353
Remaining individualsnot grpmax-eligible	0.00161%	62,264

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: DNPEP
Protein: p.Ile245Thr
Coding: c.734T>C
MANE Select: NM_012100
dbSNP: rs549968429
Type: single nucleotide variant
Location: chr2:219385464 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.95 · 1 PDB
Residue 245: a β-strand

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

Similar variants

DNPEP p.Tyr308Cys Uncertain significance ★★ ⚠ same type
DNPEP p.Ile171Val Benign ★★ same type
DNPEP p.Ala204Thr Uncertain significance ★ ⚠ same type
DNPEP p.Ala221Thr Uncertain significance ★ ⚠ same type
DNPEP p.Ala263Ser Uncertain significance ★ ⚠ same type
DNPEP p.Ala27Val Uncertain significance ★ ⚠ same type
DNPEP p.Ala321Ser Uncertain significance ★ ⚠ same type
DNPEP p.Arg114His 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/dnpep-p-ile245thr (accessed [today's date]).

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