Is SRCAP p.Arg741Cys (c.2221C>T) pathogenic?

SRCAP p.Arg741Cys (c.2221C>T) is classified Uncertain significance in SRCAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-19). AlphaMissense: ambiguous (0.4596); Very rare (popmax 0.00329%, sas); Associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities.

How common is SRCAP p.Arg741Cys (c.2221C>T) in the general population?

SRCAP p.Arg741Cys (c.2221C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about SRCAP p.Arg741Cys (c.2221C>T)?

AlphaMissense predicts ambiguous (score 0.4596) — an in-silico prediction, not a clinical call.

SRCAP p.Arg741Cys

Q: What condition is associated with SRCAP p.Arg741Cys (c.2221C>T)?

SRCAP p.Arg741Cys (c.2221C>T) is associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, Floating-Harbor syndrome (ClinVar).

c.2221C>T · rs372334206 · VCV2346617

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities

Computational evidence

Protein change
AlphaMissense	0.4596	ambiguous
REVEL	0.809	moderately pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 4,014 bp · p 9.1e-31 · regional, not allelic
Overall
CADD	27.3	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 0.00329% South Asian · 3/91,080 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00192% 31/1,614,106 alleles · very rare exomes 27/1,461,860 · genomes 4/152,246 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,360
European (non-Finnish)	0.00237%	42,144

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.Arg741Cys
Coding: c.2221C>T
MANE Select: NM_006662
dbSNP: rs372334206
Type: single nucleotide variant
Location: chr16:30713298 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 741: the helicase atp-binding domain; a UniProt-annotated variant site (in dehmba); a β-strand

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.Arg741His Uncertain significance ★★ ⚠ 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-arg741cys (accessed [today's date]).

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