Is DIAPH2 p.Pro615Leu (c.1844C>T) pathogenic?

DIAPH2 p.Pro615Leu (c.1844C>T) is classified Uncertain significance in DIAPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). AlphaMissense: likely benign (0.0665); Absent from gnomAD v4.1.

How common is DIAPH2 p.Pro615Leu (c.1844C>T) in the general population?

DIAPH2 p.Pro615Leu (c.1844C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DIAPH2 p.Pro615Leu (c.1844C>T)?

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

DIAPH2 p.Pro615Leu

c.1844C>T · VCV3271954

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

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0665	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -1.4
Regional constraint	o/e 0.89	unconstrained · MANE · 683 kb · p 0.0098 · regional, not allelic
Overall
CADD	10.86	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.

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: DIAPH2
Protein: p.Pro615Leu
Coding: c.1844C>T
MANE Select: NM_006729
Type: single nucleotide variant
Location: chrX:96958057 (GRCh38)
Structure: AlphaFold pLDDT 76.09
Residue 615: the fh1 domain

Full DIAPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIAPH2 p.Pro615Ser Uncertain significance ★ ⚠ same residue
DIAPH2 p.Ala83Thr Benign/Likely benign ★★ same type
DIAPH2 p.Ile475= Likely benign ★★ same type
DIAPH2 p.Phe504= Benign ★★ same type
DIAPH2 c.733-1G>T Uncertain significance ★ same type
DIAPH2 p.Ala125Val Uncertain significance ★ ⚠ same type
DIAPH2 p.Ala488Val Uncertain significance ★ ⚠ same type
DIAPH2 p.Ala672Thr 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/diaph2-p-pro615leu (accessed [today's date]).

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