Is SRCAP p.Arg2421His (c.7262G>A) pathogenic?

SRCAP p.Arg2421His (c.7262G>A) is classified Uncertain significance in SRCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0834); Ultra-rare (popmax 0.0167%, amr).

How common is SRCAP p.Arg2421His (c.7262G>A) in the general population?

SRCAP p.Arg2421His (c.7262G>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about SRCAP p.Arg2421His (c.7262G>A)?

AlphaMissense predicts likely benign (score 0.0834) — an in-silico prediction, not a clinical call.

SRCAP p.Arg2421His

c.7262G>A · VCV4798394

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0834 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Computational evidence

Protein change
AlphaMissense	0.0834	likely benign
REVEL	0.338	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP -0.14, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 2,598 bp · p 0.058 · regional, not allelic
Overall
CADD	22.1	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 0.0167% Admixed American · 10/60,002 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000929% 15/1,613,980 alleles · ultra-rare exomes 15/1,461,892 · genomes 0/152,088 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,000
South Asian	0.0022%	45,536
European (non-Finnish)	0.000254%	393,332

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.Arg2421His
Coding: c.7262G>A
MANE Select: NM_006662
Type: single nucleotide variant
Location: chr16:30737302 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2421: the 'disordered' region; a UniProt-annotated variant site (in dehmba); a UniProt-annotated variant site (in flhs)

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

Similar variants

SRCAP p.Arg2421= Benign/Likely benign ★★ same residue
SRCAP p.Arg2421Cys Uncertain significance ★ ⚠ same residue
SRCAP p.Arg2421Leu Likely benign ★ same residue
SRCAP p.Arg2329Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2435Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2444Ter Pathogenic ★★ same type
SRCAP p.Arg2718Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2748Ter Pathogenic ★★ same type

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-arg2421his (accessed [today's date]).

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