Is SRCAP p.Pro1233Leu (c.3698C>T) pathogenic?

SRCAP p.Pro1233Leu (c.3698C>T) is classified Uncertain significance in SRCAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-24). AlphaMissense: likely benign (0.2128); Ultra-rare (popmax 0.0165%, sas).

How common is SRCAP p.Pro1233Leu (c.3698C>T) in the general population?

SRCAP p.Pro1233Leu (c.3698C>T) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

What do computational predictors say about SRCAP p.Pro1233Leu (c.3698C>T)?

AlphaMissense predicts likely benign (score 0.2128) — an in-silico prediction, not a clinical call.

SRCAP p.Pro1233Leu

c.3698C>T · rs548463254 · VCV2646397

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2128 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Computational evidence

Protein change
AlphaMissense	0.2128	likely benign
REVEL	0.52	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 8,776 bp · p 0.24 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% South Asian · 15/91,034 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00521% 84/1,613,632 alleles · ultra-rare exomes 75/1,461,348 · genomes 9/152,284 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,069
Remaining individualsnot grpmax-eligible	0.00961%	10,409
African / African-American	0.00666%	15,008
European (non-Finnish)	0.00492%	20,343

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.Pro1233Leu
Coding: c.3698C>T
MANE Select: NM_006662
dbSNP: rs548463254
Type: single nucleotide variant
Location: chr16:30722278 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1233: a UniProt-annotated variant site (in dehmba)

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

Similar variants

SRCAP p.Pro1233= Benign/Likely benign ★★ same residue
SRCAP p.Arg2329Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2435Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2444Ter Pathogenic ★★ same type
SRCAP p.Arg2718Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2748Ter Pathogenic ★★ same type
SRCAP p.Gln2407Ter Pathogenic ★★ same type
SRCAP p.Gln2419Ter Pathogenic ★★ 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/srcap-p-pro1233leu (accessed [today's date]).

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