Is DIAPH3 p.Pro596= (c.1788T>A) pathogenic?

DIAPH3 p.Pro596= (c.1788T>A) is classified Likely benign in DIAPH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). Very rare (popmax 0.0066%, eas).

How common is DIAPH3 p.Pro596= (c.1788T>A) in the general population?

DIAPH3 p.Pro596= (c.1788T>A) is very rare (popmax 0.0066%, eas) (gnomAD).

DIAPH3 p.Pro596=

c.1788T>A · rs1594171966 · VCV761652

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0066%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.7	GERP -3.2
Overall
CADD	1.135	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0066% East Asian · 2/30,292 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00422% 59/1,396,630 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0141%	7,109
East Asiangrpmax	0.0066%	15,146
Admixed American	0.00556%	17,975
Ashkenazi Jewishnot grpmax-eligible	0.00434%	23,038
European (non-Finnish)	0.00418%	23,950
Finnishnot grpmax-eligible	0.00208%	48,148
African / African-American	0.00148%	67,708
South Asian	0.00114%	87,976

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro596=
Coding: c.1788T>A
MANE Select: NM_001042517
dbSNP: rs1594171966
Type: single nucleotide variant
Location: chr13:59971023 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.33 · 2 PDB
Residue 596: the fh1 domain; the 'disordered' region

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

Similar variants

DIAPH3 p.Pro596Leu Benign ★★ ⚠ 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-pro596 (accessed [today's date]).

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