Is DPH1 p.Pro399Leu (c.1196C>T) pathogenic?

DPH1 p.Pro399Leu (c.1196C>T) is classified Uncertain significance in DPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-25). AlphaMissense: likely benign (0.0665); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with DPH1 p.Pro399Leu (c.1196C>T)?

DPH1 p.Pro399Leu (c.1196C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DPH1 p.Pro399Leu (c.1196C>T) in the general population?

DPH1 p.Pro399Leu (c.1196C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DPH1 p.Pro399Leu (c.1196C>T)?

AlphaMissense predicts likely benign (score 0.0665) — an in-silico prediction, not a clinical call.

DPH1 p.Pro399Leu

c.1196C>T · rs2067525230 · VCV2478991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0665 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0665	likely benign
REVEL	0.023	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP -2.3
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.074 · regional, not allelic
Overall
CADD	9.788	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P404L vs ClinVar P399L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DPH1
Protein: p.Pro399Leu
Coding: c.1196C>T
MANE Select: NM_001383
dbSNP: rs2067525230
Type: single nucleotide variant
Location: chr17:2041590 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.00
Residue 399: the 'disordered' region

Full DPH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DPH1 p.Pro399Ser Uncertain significance ★ ⚠ same residue
DPH1 p.Arg144Trp Uncertain significance ★★ ⚠ same condition
DPH1 p.Ile241Phe Uncertain significance ★★ same condition
DPH1 p.Lys38Thr Likely benign ★★ same condition
DPH1 c.279-5C>T Uncertain significance ★ same condition
DPH1 c.558+4G>C Uncertain significance ★ same condition
DPH1 c.-12C>T Uncertain significance ★ ⚠ same condition
DPH1 c.-2T>A 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/dph1-p-pro399leu (accessed [today's date]).

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