Is DPM3 p.Leu14Pro (c.41T>C) pathogenic?

DPM3 p.Leu14Pro (c.41T>C) is classified Pathogenic in DPM3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-29). AlphaMissense: ambiguous (0.341); Very rare (popmax 0.0028%, nfe); Associated with DPM3-congenital disorder of glycosylation.

What condition is associated with DPM3 p.Leu14Pro (c.41T>C)?

DPM3 p.Leu14Pro (c.41T>C) is associated with DPM3-congenital disorder of glycosylation (ClinVar).

How common is DPM3 p.Leu14Pro (c.41T>C) in the general population?

DPM3 p.Leu14Pro (c.41T>C) is very rare (popmax 0.0028%, nfe) (gnomAD).

How is DPM3-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DPM3 p.Leu14Pro (c.41T>C)?

AlphaMissense predicts ambiguous (score 0.341) — an in-silico prediction, not a clinical call.

DPM3 p.Leu14Pro

c.41T>C · rs778481307 · VCV585021

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.341 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

DPM3-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.341	ambiguous
REVEL	0.884	moderately pathogenic-leaning
SaProt	LLR -12.22	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 9.2	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 275 bp · p 0.45 · regional, not allelic
Overall
CADD	29.1	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 0.0028% European (non-Finnish) · 33/1,180,048 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00204% 33/1,614,088 alleles · very rare

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: DPM3
Protein: p.Leu14Pro
Coding: c.41T>C
MANE Select: NM_153741
dbSNP: rs778481307
Type: single nucleotide variant
Location: chr1:155140200 (GRCh38)
Gene constraint: LOEUF 1.364 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.73
Residue 14: a UniProt-annotated variant site (in mddgc15; uncertain significance)

Full DPM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DPM3-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For DPM3-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

DPM3 p.Leu14= Likely benign ★ same residue
DPM3 p.Ala70Thr Uncertain significance ★★ ⚠ same condition
DPM3 p.Ala86Asp Uncertain significance ★★ ⚠ same condition
DPM3 p.Arg60Cys Uncertain significance ★★ ⚠ same condition
DPM3 p.Arg60Leu Uncertain significance ★★ ⚠ same condition
DPM3 p.Glu73Ala Uncertain significance ★★ ⚠ same condition
DPM3 p.Gly89Glu Uncertain significance ★★ ⚠ same condition
DPM3 p.Trp7Arg Uncertain significance ★★ ⚠ same condition

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/dpm3-p-leu14pro (accessed [today's date]).

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