Is SRCAP p.Ser21Leu (c.62C>T) pathogenic?

SRCAP p.Ser21Leu (c.62C>T) is classified Conflicting classifications of pathogenicity in SRCAP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-03-17). AlphaMissense: likely benign (0.1696); Ultra-rare (popmax 0.0245%, eas); Associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities.

How common is SRCAP p.Ser21Leu (c.62C>T) in the general population?

SRCAP p.Ser21Leu (c.62C>T) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about SRCAP p.Ser21Leu (c.62C>T)?

AlphaMissense predicts likely benign (score 0.1696) — an in-silico prediction, not a clinical call.

SRCAP p.Ser21Leu

Q: What condition is associated with SRCAP p.Ser21Leu (c.62C>T)?

SRCAP p.Ser21Leu (c.62C>T) is associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, Floating-Harbor syndrome (ClinVar).

c.62C>T · rs183497403 · VCV197283

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Conditions

developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities

Computational evidence

Protein change
AlphaMissense	0.1696	likely benign
REVEL	0.332	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,462 bp · p 0.64 · regional, not allelic
Overall
CADD	25.4	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 0.0245% East Asian · 11/44,872 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.0126% 203/1,612,824 alleles · ultra-rare exomes 197/1,460,506 · genomes 6/152,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,079
European (non-Finnish)	0.0159%	6,306
Remaining individualsnot grpmax-eligible	0.0048%	20,816
African / African-American	0.00133%	75,036
South Asian	0.0011%	90,900

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.Ser21Leu
Coding: c.62C>T
MANE Select: NM_006662
dbSNP: rs183497403
Type: single nucleotide variant
Location: chr16:30704071 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 21: the 'disordered' region

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

Also linked: Floating-Harbor syndrome

Similar variants

SRCAP p.Ser21= Likely benign ★ same residue
SRCAP p.Arg2329Ter Pathogenic/Likely pathogenic ★★ same condition
SRCAP p.Arg2435Ter Pathogenic/Likely pathogenic ★★ same condition
SRCAP p.Arg2444Ter Pathogenic ★★ same condition
SRCAP p.Arg2718Ter Pathogenic/Likely pathogenic ★★ same condition
SRCAP p.Arg2748Ter Pathogenic ★★ same condition
SRCAP p.Gln2407Ter Pathogenic ★★ same condition
SRCAP p.Gln2419Ter Pathogenic ★★ 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-ser21leu (accessed [today's date]).

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