Is SRCAP p.Arg1224Cys (c.3670C>T) pathogenic?

SRCAP p.Arg1224Cys (c.3670C>T) is classified Uncertain significance in SRCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-06). AlphaMissense: likely pathogenic (0.703); Very rare (popmax 0.00445%, eas).

How common is SRCAP p.Arg1224Cys (c.3670C>T) in the general population?

SRCAP p.Arg1224Cys (c.3670C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about SRCAP p.Arg1224Cys (c.3670C>T)?

AlphaMissense predicts likely pathogenic (score 0.703) — an in-silico prediction, not a clinical call.

SRCAP p.Arg1224Cys

c.3670C>T · rs766377461 · VCV1362547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.703	likely pathogenic
REVEL	0.68	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.77 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 8,776 bp · p 0.24 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00445% East Asian · 2/44,894 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000867% 14/1,614,002 alleles · very rare exomes 12/1,461,830 · genomes 2/152,172 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,447
Finnishnot grpmax-eligible	0.00156%	64,022
African / African-American	0.00133%	74,926
South Asian	0.0011%	91,078
European (non-Finnish)	0.000763%	131,113

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.Arg1224Cys
Coding: c.3670C>T
MANE Select: NM_006662
dbSNP: rs766377461
Type: single nucleotide variant
Location: chr16:30722250 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1224: a UniProt-annotated variant site (in dehmba)

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

Similar variants

SRCAP p.Arg1224His Uncertain significance ★★ 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
SRCAP p.Gln2407Ter Pathogenic ★★ same type
SRCAP p.Gln2419Ter 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-arg1224cys (accessed [today's date]).

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