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

DSCAM p.Pro596Leu (c.1787C>T) is classified Uncertain significance in DSCAM (ClinVar, Single submitter, 2 submitters; last evaluated 2023-06-12). AlphaMissense: ambiguous (0.4753); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with DSCAM p.Pro596Leu (c.1787C>T)?

DSCAM p.Pro596Leu (c.1787C>T) is associated with Inborn genetic diseases (ClinVar).

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

DSCAM p.Pro596Leu (c.1787C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

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

AlphaMissense predicts ambiguous (score 0.4753) — an in-silico prediction, not a clinical call.

DSCAM p.Pro596Leu

c.1787C>T · rs1182107464 · VCV2512714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4753	ambiguous
REVEL	0.6	indeterminate
SaProt	LLR -14.99	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 149 kb · p 1.9e-14 · regional, not allelic
Overall
CADD	28.5	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 0.0022% South Asian · 2/91,022 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000496% 8/1,612,306 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,511
European (non-Finnish)	0.000509%	196,480

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: DSCAM
Protein: p.Pro596Leu
Coding: c.1787C>T
MANE Select: NM_001389
dbSNP: rs1182107464
Type: single nucleotide variant
Location: chr21:40312356 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 69.98 · 1 PDB
Residue 596: the ig-like c2-type 7 domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DSCAM p.Pro596= Likely benign ★ same residue
DSCAM p.Ser682Arg Uncertain significance ★★ ⚠ same condition
DSCAM p.Gly1960Glu Likely benign ★★ same condition
DSCAM p.Val757Leu Likely benign ★★ same condition
DSCAM p.Arg1754Ter Pathogenic ★ same condition
DSCAM c.3850+4G>C Uncertain significance ★ same condition
DSCAM c.4889-4C>G Uncertain significance ★ same condition
DSCAM c.5185+2T>A Uncertain significance ★ same condition

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/dscam-p-pro596leu (accessed [today's date]).

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