Is SRCAP p.Arg1854His (c.5561G>A) pathogenic?

SRCAP p.Arg1854His (c.5561G>A) is classified Conflicting classifications of pathogenicity in SRCAP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2028); Ultra-rare (popmax 0.0147%, afr); Associated with Inborn genetic diseases.

What condition is associated with SRCAP p.Arg1854His (c.5561G>A)?

SRCAP p.Arg1854His (c.5561G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SRCAP p.Arg1854His (c.5561G>A) in the general population?

SRCAP p.Arg1854His (c.5561G>A) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about SRCAP p.Arg1854His (c.5561G>A)?

AlphaMissense predicts likely benign (score 0.2028) — an in-silico prediction, not a clinical call.

SRCAP p.Arg1854His

c.5561G>A · rs746926335 · VCV2436481

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2028 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2028	likely benign
REVEL	0.381	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 8,776 bp · p 0.24 · regional, not allelic
Overall
CADD	23.1	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 0.0147% African / African-American · 11/74,878 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00634%

Overall 0.00149% 24/1,613,984 alleles · ultra-rare exomes 18/1,461,884 · genomes 6/152,100 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,807
Admixed American	0.00667%	14,999
South Asian	0.0011%	91,082
European (non-Finnish)	0.000678%	147,504

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.Arg1854His
Coding: c.5561G>A
MANE Select: NM_006662
dbSNP: rs746926335
Type: single nucleotide variant
Location: chr16:30724985 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1854: 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

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

Similar variants

SRCAP p.Arg1854Leu Uncertain significance ★★ same residue
SRCAP p.Arg1854Cys Uncertain significance ★ same residue
SRCAP p.Arg1854= Likely benign ★ 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-arg1854his (accessed [today's date]).

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