Is SRCAP p.Arg709Trp (c.2125C>T) pathogenic?

SRCAP p.Arg709Trp (c.2125C>T) is classified Uncertain significance in SRCAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-11-01). AlphaMissense: likely pathogenic (0.9991); No allele count reported in gnomAD v4.1 (AN 1,614,024); Associated with Floating-Harbor syndrome.

What condition is associated with SRCAP p.Arg709Trp (c.2125C>T)?

SRCAP p.Arg709Trp (c.2125C>T) is associated with Floating-Harbor syndrome, developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (ClinVar).

How common is SRCAP p.Arg709Trp (c.2125C>T) in the general population?

SRCAP p.Arg709Trp (c.2125C>T) is no allele count reported in gnomAD v4.1 (AN 1,614,024) (gnomAD).

What do computational predictors say about SRCAP p.Arg709Trp (c.2125C>T)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

SRCAP p.Arg709Trp

c.2125C>T · rs760183638 · VCV1033131

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,024)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Floating-Harbor syndrome

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic · top 3% in SRCAP
REVEL	0.78	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.45 · evaluated, not missing
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	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,614,024). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SRCAP
Protein: p.Arg709Trp
Coding: c.2125C>T
MANE Select: NM_006662
dbSNP: rs760183638
Type: single nucleotide variant
Location: chr16:30712810 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 709: the helicase atp-binding domain; a UniProt-annotated variant site (in dehmba); an α-helix

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

Disease context

Floating-Harbor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities

Similar variants

SRCAP p.Arg709Gln 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-arg709trp (accessed [today's date]).

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