Is DPH1 p.Leu159Pro (c.476T>C) pathogenic?

DPH1 p.Leu159Pro (c.476T>C) is classified Pathogenic in DPH1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-09-30). AlphaMissense: likely pathogenic (0.9622); Absent from gnomAD v4.1; Associated with developmental delay with short stature, dysmorphic facial features, and sparse hair 1.

How common is DPH1 p.Leu159Pro (c.476T>C) in the general population?

DPH1 p.Leu159Pro (c.476T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DPH1 p.Leu159Pro (c.476T>C)?

AlphaMissense predicts likely pathogenic (score 0.9622) — an in-silico prediction, not a clinical call.

DPH1 p.Leu159Pro

Q: What condition is associated with DPH1 p.Leu159Pro (c.476T>C)?

DPH1 p.Leu159Pro (c.476T>C) is associated with developmental delay with short stature, dysmorphic facial features, and sparse hair 1 (ClinVar).

c.476T>C · rs2067429826 · VCV997985

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9622 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

developmental delay with short stature, dysmorphic facial features, and sparse hair 1

Computational evidence

Protein change
AlphaMissense	0.9622	likely pathogenic ✓ concordant with ClinVar · top 9% in DPH1
REVEL	0.654	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.074 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L164P vs ClinVar L159P) — 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.Leu159Pro
Coding: c.476T>C
MANE Select: NM_001383
dbSNP: rs2067429826
Type: single nucleotide variant
Location: chr17:2036604 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.00
Residue 159: a UniProt-annotated variant site (in dedssh1; impairs diphthamide modification of elongation factor 2)

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

Disease context

developmental delay with short stature, dysmorphic facial features, and sparse hair 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DPH1 p.Leu159Phe Uncertain significance ★ ⚠ same residue
DPH1 p.Leu229Pro Pathogenic/Likely pathogenic ★★ same condition
DPH1 p.Arg144Trp Uncertain significance ★★ ⚠ same condition
DPH1 p.Arg22Gln Uncertain significance ★★ ⚠ same condition
DPH1 p.Arg47Trp Uncertain significance ★★ ⚠ same condition
DPH1 p.Asp231Glu Uncertain significance ★★ ⚠ same condition
DPH1 p.Gln269His Uncertain significance ★★ ⚠ same condition
DPH1 c.400+1G>A Likely pathogenic ★ 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-leu159pro (accessed [today's date]).

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