Is SRCAP p.Arg858His (c.2573G>A) pathogenic?

SRCAP p.Arg858His (c.2573G>A) is classified Conflicting classifications of pathogenicity in SRCAP (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.1176); Rare (popmax 0.187%, afr); Associated with Inborn genetic diseases.

What condition is associated with SRCAP p.Arg858His (c.2573G>A)?

SRCAP p.Arg858His (c.2573G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SRCAP p.Arg858His (c.2573G>A) in the general population?

SRCAP p.Arg858His (c.2573G>A) is rare (popmax 0.187%, afr) (gnomAD).

What do computational predictors say about SRCAP p.Arg858His (c.2573G>A)?

AlphaMissense predicts likely benign (score 0.1176) — an in-silico prediction, not a clinical call.

SRCAP p.Arg858His

c.2573G>A · rs35892240 · VCV499747

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1176 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.187%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1176	likely benign
REVEL	0.503	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 4,608 bp · p 6.7e-06 · regional, not allelic
Overall
CADD	27.9	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 0.187% African / African-American · 140/75,048 alleles

Filtering AF 0.161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.152%

Overall 0.0427% 690/1,614,176 alleles · rare exomes 604/1,461,894 · genomes 86/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.187%	536
European (non-Finnish)	0.0436%	2,291
Remaining individualsnot grpmax-eligible	0.0416%	2,404
East Asian	0.00891%	11,222
Finnishnot grpmax-eligible	0.00625%	16,008
Admixed American	0.00167%	60,010

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.Arg858His
Coding: c.2573G>A
MANE Select: NM_006662
dbSNP: rs35892240
Type: single nucleotide variant
Location: chr16:30716145 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 858: a β-strand; 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.Arg858Cys Conflicting classifications of pathogenicity ★ same residue
SRCAP p.Arg858= 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
SRCAP p.Ala1985Thr 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-arg858his (accessed [today's date]).

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