Is DPH2 p.Arg49Pro (c.146G>C) pathogenic?

DPH2 p.Arg49Pro (c.146G>C) is classified Uncertain significance in DPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-15). AlphaMissense: ambiguous (0.4414); Very rare (popmax 0.000254%, nfe).

How common is DPH2 p.Arg49Pro (c.146G>C) in the general population?

DPH2 p.Arg49Pro (c.146G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about DPH2 p.Arg49Pro (c.146G>C)?

AlphaMissense predicts ambiguous (score 0.4414) — an in-silico prediction, not a clinical call.

DPH2 p.Arg49Pro

c.146G>C · VCV4244418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4414 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4414	ambiguous
REVEL	0.27	benign-leaning
SaProt	LLR -13.99	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.32 · evaluated, not missing
Pangolin	Δ0.22	loss · gain 0.15 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 5.2	GERP 0.87, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,712 bp · p 0.054 · regional, not allelic
Overall
CADD	25.6	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 0.000254% European (non-Finnish) · 3/1,179,896 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,582 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: DPH2
Protein: p.Arg49Pro
Coding: c.146G>C
MANE Select: NM_001384
Type: single nucleotide variant
Location: chr1:43970321 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.60

Full DPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DPH2 p.Arg201His Uncertain significance ★★ ⚠ same type
DPH2 p.Arg477Ter Likely pathogenic ★ same type
DPH2 p.Ser75Ter Likely pathogenic ★ same type
DPH2 p.Ala310Val Uncertain significance ★ ⚠ same type
DPH2 p.Ala345Thr Uncertain significance ★ ⚠ same type
DPH2 p.Ala448Thr Uncertain significance ★ ⚠ same type
DPH2 p.Arg125His Uncertain significance ★ ⚠ same type
DPH2 p.Arg169Cys 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/dph2-p-arg49pro (accessed [today's date]).

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