Is DPH1 p.Leu146Pro (c.437T>C) pathogenic?

DPH1 p.Leu146Pro (c.437T>C) is classified Uncertain significance in DPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-11). AlphaMissense: likely pathogenic (0.9745); Absent from gnomAD v4.1.

How common is DPH1 p.Leu146Pro (c.437T>C) in the general population?

DPH1 p.Leu146Pro (c.437T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DPH1 p.Leu146Pro (c.437T>C)?

AlphaMissense predicts likely pathogenic (score 0.9745) — an in-silico prediction, not a clinical call.

DPH1 p.Leu146Pro

c.437T>C · rs2543514160 · VCV2579545

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9745 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.9745	likely pathogenic · top 7% in DPH1
REVEL	0.781	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.26 · evaluated, not missing
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	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 L151P vs ClinVar L146P) — 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.Leu146Pro
Coding: c.437T>C
MANE Select: NM_001383
dbSNP: rs2543514160
Type: single nucleotide variant
Location: chr17:2036565 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.00

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

Similar variants

DPH1 p.Leu229Pro Pathogenic/Likely pathogenic ★★ same type
DPH1 p.Arg144Trp Uncertain significance ★★ ⚠ same type
DPH1 p.Arg22Gln Uncertain significance ★★ ⚠ same type
DPH1 p.Arg27His Uncertain significance ★★ ⚠ same type
DPH1 p.Arg47Trp Uncertain significance ★★ ⚠ same type
DPH1 p.Asp231Glu Uncertain significance ★★ ⚠ same type
DPH1 p.Gln269His Uncertain significance ★★ ⚠ same type
DPH1 p.Ile241Phe 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/dph1-p-leu146pro (accessed [today's date]).

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