Is SRCAP p.Arg325His (c.974G>A) pathogenic?

SRCAP p.Arg325His (c.974G>A) is classified Uncertain significance in SRCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-25). AlphaMissense: likely benign (0.1322); Very rare (popmax 8.47e-05%, nfe).

How common is SRCAP p.Arg325His (c.974G>A) in the general population?

SRCAP p.Arg325His (c.974G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SRCAP p.Arg325His (c.974G>A)?

AlphaMissense predicts likely benign (score 0.1322) — an in-silico prediction, not a clinical call.

SRCAP p.Arg325His

c.974G>A · rs770702011 · VCV2694590

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1322 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.1322	likely benign
REVEL	0.335	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 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 127 bp · p 0.0011 · regional, not allelic
Overall
CADD	24.4	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 8.47e-05% European (non-Finnish) · 1/1,180,040 alleles

Overall 0.000124% 2/1,614,062 alleles · very rare exomes 1/1,461,888 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)grpmax	8.47e-05%	1,180,040

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg325His
Coding: c.974G>A
MANE Select: NM_006662
dbSNP: rs770702011
Type: single nucleotide variant
Location: chr16:30709968 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 325: the 'disordered' region

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

Similar variants

SRCAP p.Arg325Cys 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-arg325his (accessed [today's date]).

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