Is SRCAP p.Arg3226Cys (c.9676C>T) pathogenic?

SRCAP p.Arg3226Cys (c.9676C>T) is classified Conflicting classifications of pathogenicity in SRCAP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-30). AlphaMissense: likely pathogenic (0.5947); Ultra-rare (popmax 0.0147%, amr); Associated with Inborn genetic diseases.

What condition is associated with SRCAP p.Arg3226Cys (c.9676C>T)?

SRCAP p.Arg3226Cys (c.9676C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SRCAP p.Arg3226Cys (c.9676C>T) in the general population?

SRCAP p.Arg3226Cys (c.9676C>T) is ultra-rare (popmax 0.0147%, amr) (gnomAD).

What do computational predictors say about SRCAP p.Arg3226Cys (c.9676C>T)?

AlphaMissense predicts likely pathogenic (score 0.5947) — an in-silico prediction, not a clinical call.

SRCAP p.Arg3226Cys

c.9676C>T · rs746006737 · VCV2636026

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5947 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5947	likely pathogenic
REVEL	0.629	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 2,598 bp · p 0.058 · regional, not allelic
Overall
CADD	28.2	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 0.0147% Admixed American · 6/40,872 alleles

Filtering AF 0.00636% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00435%

Overall 0.00174% 26/1,492,702 alleles · ultra-rare exomes 22/1,340,452 · genomes 4/152,250 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0147%	6,812
African / African-American	0.00423%	23,634
South Asian	0.00268%	37,359
Remaining individualsnot grpmax-eligible	0.00175%	57,260
European (non-Finnish)	0.00125%	80,137

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.Arg3226Cys
Coding: c.9676C>T
MANE Select: NM_006662
dbSNP: rs746006737
Type: single nucleotide variant
Location: chr16:30739716 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 3226: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SRCAP p.Arg3226His Uncertain significance ★★ same residue
SRCAP p.Arg3226Leu Uncertain significance ★★ same residue
SRCAP p.Arg3226Gly Uncertain significance ★ same residue
SRCAP p.Gln2407Ter Pathogenic ★★ same condition
SRCAP p.Ala1152Val Uncertain significance ★★ ⚠ same condition
SRCAP p.Ala1161Thr Uncertain significance ★★ ⚠ same condition
SRCAP p.Ala1570Thr Uncertain significance ★★ ⚠ same condition
SRCAP p.Ala1584Gly 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-arg3226cys (accessed [today's date]).

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