Is SRCAP p.Ser2539Leu (c.7616C>T) pathogenic?

SRCAP p.Ser2539Leu (c.7616C>T) is classified Uncertain significance in SRCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). AlphaMissense: likely benign (0.0839); Very rare (popmax 0.00329%, sas); Associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities.

How common is SRCAP p.Ser2539Leu (c.7616C>T) in the general population?

SRCAP p.Ser2539Leu (c.7616C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about SRCAP p.Ser2539Leu (c.7616C>T)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

SRCAP p.Ser2539Leu

Q: What condition is associated with SRCAP p.Ser2539Leu (c.7616C>T)?

SRCAP p.Ser2539Leu (c.7616C>T) is associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (ClinVar).

c.7616C>T · VCV3367026

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.126	moderately 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 1.2	GERP -0.64, phastCons 0.001
Regional constraint	o/e 1.06	unconstrained · MANE · 2,598 bp · p 0.058 · regional, not allelic
Overall
CADD	13.78	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 0.00329% South Asian · 3/91,088 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000372% 6/1,613,998 alleles · very rare exomes 5/1,461,828 · genomes 1/152,170 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,363
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000169%	590,016

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.Ser2539Leu
Coding: c.7616C>T
MANE Select: NM_006662
Type: single nucleotide variant
Location: chr16:30737656 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2539: a UniProt-annotated variant site (in dehmba); a UniProt-annotated variant site (in flhs)

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

Disease context

developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SRCAP p.Arg2444Ter Pathogenic ★★ same condition
SRCAP p.Arg2718Ter Pathogenic/Likely pathogenic ★★ same condition
SRCAP c.2130+6A>T Uncertain significance ★★ same condition
SRCAP c.492+3A>G Uncertain significance ★★ same condition
SRCAP p.Ala1161Thr Uncertain significance ★★ ⚠ same condition
SRCAP p.Ala1451Thr Uncertain significance ★★ ⚠ same condition
SRCAP p.Ala1461Val Uncertain significance ★★ same condition
SRCAP p.Ala1802Thr 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-ser2539leu (accessed [today's date]).

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