Is SRCAP p.Ser1826Leu (c.5477C>T) pathogenic?

SRCAP p.Ser1826Leu (c.5477C>T) is classified Uncertain significance in SRCAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-23). AlphaMissense: likely benign (0.1026); Ultra-rare (popmax 0.0527%, sas); Associated with Floating-Harbor syndrome.

What condition is associated with SRCAP p.Ser1826Leu (c.5477C>T)?

SRCAP p.Ser1826Leu (c.5477C>T) is associated with Floating-Harbor syndrome, developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (ClinVar).

How common is SRCAP p.Ser1826Leu (c.5477C>T) in the general population?

SRCAP p.Ser1826Leu (c.5477C>T) is ultra-rare (popmax 0.0527%, sas) (gnomAD).

What do computational predictors say about SRCAP p.Ser1826Leu (c.5477C>T)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

SRCAP p.Ser1826Leu

c.5477C>T · rs374858506 · VCV1501065

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0527%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Floating-Harbor syndrome

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.204	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 8,776 bp · p 0.24 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.0527% South Asian · 48/91,084 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.0107% 173/1,614,212 alleles · ultra-rare exomes 163/1,461,890 · genomes 10/152,322 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0527%	1,898
European (non-Finnish)	0.01%	10,000
Admixed American	0.00666%	15,009
Remaining individualsnot grpmax-eligible	0.0032%	31,255
Finnishnot grpmax-eligible	0.00156%	64,042

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.Ser1826Leu
Coding: c.5477C>T
MANE Select: NM_006662
dbSNP: rs374858506
Type: single nucleotide variant
Location: chr16:30724901 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1826: a UniProt-annotated variant site (in dehmba)

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.Ser1826= 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-ser1826leu (accessed [today's date]).

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