Is SRCAP p.Pro1647Leu (c.4940C>T) pathogenic?

SRCAP p.Pro1647Leu (c.4940C>T) is classified Conflicting classifications of pathogenicity in SRCAP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0603); Very rare (popmax 0.00933%, afr); Associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities.

How common is SRCAP p.Pro1647Leu (c.4940C>T) in the general population?

SRCAP p.Pro1647Leu (c.4940C>T) is very rare (popmax 0.00933%, afr) (gnomAD).

What do computational predictors say about SRCAP p.Pro1647Leu (c.4940C>T)?

AlphaMissense predicts likely benign (score 0.0603) — an in-silico prediction, not a clinical call.

SRCAP p.Pro1647Leu

Q: What condition is associated with SRCAP p.Pro1647Leu (c.4940C>T)?

SRCAP p.Pro1647Leu (c.4940C>T) is associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, Floating-Harbor syndrome (ClinVar).

c.4940C>T · rs200403976 · VCV318883

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0603 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00933%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities

Computational evidence

Protein change
AlphaMissense	0.0603	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.6	GERP -2.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 8,776 bp · p 0.24 · regional, not allelic
Overall
CADD	10.94	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 0.00933% African / African-American · 7/75,032 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00217% 35/1,614,168 alleles · very rare exomes 26/1,461,890 · genomes 9/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00933%	10,719
Admixed American	0.00333%	30,010
Remaining individualsnot grpmax-eligible	0.0032%	31,252
East Asian	0.00223%	44,884
European (non-Finnish)	0.00186%	53,638
South Asian	0.0011%	91,082

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.Pro1647Leu
Coding: c.4940C>T
MANE Select: NM_006662
dbSNP: rs200403976
Type: single nucleotide variant
Location: chr16:30724364 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1647: the 'disordered' region; a UniProt-annotated variant site (in dehmba)

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.Pro1647= Likely benign ★★ same residue
SRCAP p.Pro1647Ser 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

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-pro1647leu (accessed [today's date]).

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