Is SRCAP p.Pro1500Leu (c.4499C>T) pathogenic?

SRCAP p.Pro1500Leu (c.4499C>T) is classified Uncertain significance in SRCAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-14). AlphaMissense: likely benign (0.11); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with SRCAP p.Pro1500Leu (c.4499C>T)?

SRCAP p.Pro1500Leu (c.4499C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SRCAP p.Pro1500Leu (c.4499C>T) in the general population?

SRCAP p.Pro1500Leu (c.4499C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about SRCAP p.Pro1500Leu (c.4499C>T)?

AlphaMissense predicts likely benign (score 0.11) — an in-silico prediction, not a clinical call.

SRCAP p.Pro1500Leu

c.4499C>T · rs770748860 · VCV1486912

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.11 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.11	likely benign
REVEL	0.283	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.7, phastCons 0.99
Regional constraint	o/e 1.03	unconstrained · MANE · 8,776 bp · p 0.24 · regional, not allelic
Overall
CADD	23.9	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,002 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00217% 35/1,614,036 alleles · very rare exomes 33/1,461,868 · genomes 2/152,168 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
South Asian	0.00659%	15,181
European (non-Finnish)	0.00195%	51,306
Finnishnot grpmax-eligible	0.00156%	64,024
African / African-American	0.00134%	74,896

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: SRCAP
Protein: p.Pro1500Leu
Coding: c.4499C>T
MANE Select: NM_006662
dbSNP: rs770748860
Type: single nucleotide variant
Location: chr16:30723923 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1500: a UniProt-annotated variant site (in dehmba)

Full SRCAP 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

SRCAP p.Pro1500Ala Uncertain significance ★ ⚠ same residue
SRCAP p.Gln2407Ter Pathogenic ★★ same condition
SRCAP p.Ala1152Val Uncertain significance ★★ ⚠ same condition
SRCAP p.Ala1161Thr Uncertain significance ★★ ⚠ same condition
SRCAP p.Ala1570Thr Uncertain significance ★★ ⚠ same condition
SRCAP p.Ala1584Gly Uncertain significance ★★ same condition
SRCAP p.Ala1985Thr Uncertain significance ★★ same condition
SRCAP p.Ala2699Val 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/srcap-p-pro1500leu (accessed [today's date]).

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