Is SRCAP p.Val2222Met (c.6664G>A) pathogenic?

SRCAP p.Val2222Met (c.6664G>A) is classified Benign/Likely benign in SRCAP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0736); Rare (popmax 0.248%, amr); Associated with Floating-Harbor syndrome.

What condition is associated with SRCAP p.Val2222Met (c.6664G>A)?

SRCAP p.Val2222Met (c.6664G>A) is associated with Floating-Harbor syndrome, developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (ClinVar).

How common is SRCAP p.Val2222Met (c.6664G>A) in the general population?

SRCAP p.Val2222Met (c.6664G>A) is rare (popmax 0.248%, amr) (gnomAD).

What do computational predictors say about SRCAP p.Val2222Met (c.6664G>A)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

SRCAP p.Val2222Met

c.6664G>A · rs201837401 · VCV1561223

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.248%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Floating-Harbor syndrome

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.064	moderately 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 0.82	GERP -1.8, phastCons 0.05
Regional constraint	o/e 1.16	unconstrained · MANE · 1,692 bp · p 0.27 · regional, not allelic
Overall
CADD	17.96	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 0.248% Admixed American · 149/59,980 alleles

Filtering AF 0.216% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.203%

Overall 0.0119% 192/1,613,882 alleles · rare exomes 178/1,461,846 · genomes 14/152,036 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.248%	403
East Asian	0.0178%	5,607
Remaining individualsnot grpmax-eligible	0.0096%	10,418
African / African-American	0.00534%	18,736
European (non-Finnish)	0.00212%	47,199

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.Val2222Met
Coding: c.6664G>A
MANE Select: NM_006662
dbSNP: rs201837401
Type: single nucleotide variant
Location: chr16:30734550 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2222: 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

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.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
SRCAP p.Gln2665Ter Pathogenic/Likely 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-val2222met (accessed [today's date]).

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