Is SRCAP p.Arg741His (c.2222G>A) pathogenic?

SRCAP p.Arg741His (c.2222G>A) is classified Uncertain significance in SRCAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.2915); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with SRCAP p.Arg741His (c.2222G>A)?

SRCAP p.Arg741His (c.2222G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SRCAP p.Arg741His (c.2222G>A) in the general population?

SRCAP p.Arg741His (c.2222G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SRCAP p.Arg741His (c.2222G>A)?

AlphaMissense predicts likely benign (score 0.2915) — an in-silico prediction, not a clinical call.

SRCAP p.Arg741His

c.2222G>A · rs754805776 · VCV2898839

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2915	likely benign
REVEL	0.678	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.7, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 4,014 bp · p 9.1e-31 · regional, not allelic
Overall
CADD	25.7	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 0.00167% Admixed American · 1/60,006 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000805% 13/1,614,146 alleles · very rare exomes 13/1,461,882 · genomes 0/152,264 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,006
Finnishnot grpmax-eligible	0.00156%	64,020
African / African-American	0.00133%	75,040
European (non-Finnish)	0.000847%	118,004

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.Arg741His
Coding: c.2222G>A
MANE Select: NM_006662
dbSNP: rs754805776
Type: single nucleotide variant
Location: chr16:30713299 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 741: the helicase atp-binding domain; a UniProt-annotated variant site (in dehmba); a β-strand

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.Arg741Cys 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
SRCAP p.Ala1985Thr Uncertain significance ★★ same condition
SRCAP p.Ala2699Val 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-arg741his (accessed [today's date]).

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