Is DIAPH3 p.Arg7Pro (c.20G>C) pathogenic?

DIAPH3 p.Arg7Pro (c.20G>C) is classified Uncertain significance in DIAPH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely benign (0.1135); Very rare (popmax 0.00134%, afr).

How common is DIAPH3 p.Arg7Pro (c.20G>C) in the general population?

DIAPH3 p.Arg7Pro (c.20G>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about DIAPH3 p.Arg7Pro (c.20G>C)?

AlphaMissense predicts likely benign (score 0.1135) — an in-silico prediction, not a clinical call.

DIAPH3 p.Arg7Pro

c.20G>C · VCV3501796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1135 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1135	likely benign
REVEL	0.43	indeterminate
SaProt	LLR -5.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	phastCons 0.98
Regional constraint	o/e 1.01	unconstrained · MANE · 497 kb · p 0.83 · regional, not allelic
Overall
CADD	23.2	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

Grpmax group 0.00134% African / African-American · 1/74,662 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000188% 3/1,597,070 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,662
European (non-Finnish)	0.000171%	586,307

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: DIAPH3
Protein: p.Arg7Pro
Coding: c.20G>C
MANE Select: NM_001042517
Type: single nucleotide variant
Location: chr13:60163747 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.33 · 2 PDB
Residue 7: the 'disordered' region

Full DIAPH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIAPH3 p.Arg7Gln Uncertain significance ★ ⚠ same residue
DIAPH3 p.Ala500Val Uncertain significance ★★ ⚠ same type
DIAPH3 p.Ala546Thr Uncertain significance ★★ ⚠ same type
DIAPH3 p.Arg1027His Uncertain significance ★★ ⚠ same type
DIAPH3 p.Arg1048Cys Uncertain significance ★★ ⚠ same type
DIAPH3 p.Arg1048Gly Uncertain significance ★★ ⚠ same type
DIAPH3 p.Arg1089Pro Uncertain significance ★★ ⚠ same type
DIAPH3 p.Arg1191Ter 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/diaph3-p-arg7pro (accessed [today's date]).

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