Is DIAPH3 p.Pro596Leu (c.1787C>T) pathogenic?

DIAPH3 p.Pro596Leu (c.1787C>T) is classified Benign in DIAPH3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.0959); Low-frequency (popmax 3.16%, sas).

How common is DIAPH3 p.Pro596Leu (c.1787C>T) in the general population?

DIAPH3 p.Pro596Leu (c.1787C>T) is low-frequency (popmax 3.16%, sas) (gnomAD).

What do computational predictors say about DIAPH3 p.Pro596Leu (c.1787C>T)?

AlphaMissense predicts likely benign (score 0.0959) — an in-silico prediction, not a clinical call.

DIAPH3 p.Pro596Leu

c.1787C>T · rs150023947 · VCV513194

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0959 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.16%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0959	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -9.60	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 6.2	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 497 kb · p 0.83 · regional, not allelic
Overall
CADD	22.5	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 3.16% South Asian · 2,875/91,066 alleles

Filtering AF 3.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.02%

Overall 0.618% 9,976/1,613,752 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	4.61%	22
South Asiangrpmax	3.16%	32
Ashkenazi Jewishnot grpmax-eligible	2.97%	34
Middle Eastern	1.14%	87
Remaining individualsnot grpmax-eligible	0.859%	116
Admixed American	0.455%	220
European (non-Finnish)	0.438%	228
Finnishnot grpmax-eligible	0.122%	821
African / African-American	0.0733%	1,364
East Asian	0.00893%	11,203

Amish 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.Pro596Leu
Coding: c.1787C>T
MANE Select: NM_001042517
dbSNP: rs150023947
Type: single nucleotide variant
Location: chr13:59971024 (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.Pro596= Likely 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-pro596leu (accessed [today's date]).

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