Is SRCAP p.Pro1879fs (c.5633dup) pathogenic?

SRCAP p.Pro1879fs (c.5633dup) is classified Pathogenic/Likely pathogenic in SRCAP (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-05-08). Ultra-rare (popmax 0.0333%, mid); Associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities.

How common is SRCAP p.Pro1879fs (c.5633dup) in the general population?

SRCAP p.Pro1879fs (c.5633dup) is ultra-rare (popmax 0.0333%, mid) (gnomAD).

SRCAP p.Pro1879fs

Q: What condition is associated with SRCAP p.Pro1879fs (c.5633dup)?

SRCAP p.Pro1879fs (c.5633dup) is associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, Floating-Harbor syndrome, neurodevelopmental disorder (ClinVar).

c.5633dup · rs748467821 · VCV995431

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, mid)

Conditions

developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 25 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.9	GERP -4.6, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Middle Eastern · 2/6,012 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0173%

Overall 0.0186% 297/1,597,506 alleles · ultra-rare exomes 295/1,446,158 · genomes 2/151,348 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.121%	828
Ashkenazi Jewishnot grpmax-eligible	0.041%	2,437
Middle Easterngrpmax	0.0333%	3,006
Admixed American	0.032%	3,128
South Asian	0.0244%	4,099
European (non-Finnish)	0.0132%	7,584
Remaining individualsnot grpmax-eligible	0.0129%	7,738
African / African-American	0.00538%	18,603

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1879fs
Coding: c.5633dup
MANE Select: NM_006662
dbSNP: rs748467821
Type: Duplication
Location: chr16:30725049 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1879: 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 neurodevelopmental disorder

Similar variants

SRCAP p.Ala2409fs Likely pathogenic ★ same condition
SRCAP p.Gln1247fs Likely pathogenic ★ same condition
SRCAP p.Gly2377fs Likely pathogenic ★ same condition
SRCAP p.Leu2127fs Likely pathogenic ★ same condition
SRCAP p.Pro2916fs Likely pathogenic ★ same condition
SRCAP p.Val826fs Likely pathogenic ★ same condition
SRCAP c.1134+3dup Uncertain significance ★ same condition
SRCAP c.6729+9dup 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-pro1879fs (accessed [today's date]).

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