Is SRCAP p.Arg389His (c.1166G>A) pathogenic?

SRCAP p.Arg389His (c.1166G>A) is classified Conflicting classifications of pathogenicity in SRCAP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-04-29). AlphaMissense: likely benign (0.0743); Ultra-rare (popmax 0.0307%, afr); Associated with Inborn genetic diseases.

What condition is associated with SRCAP p.Arg389His (c.1166G>A)?

SRCAP p.Arg389His (c.1166G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SRCAP p.Arg389His (c.1166G>A) in the general population?

SRCAP p.Arg389His (c.1166G>A) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

What do computational predictors say about SRCAP p.Arg389His (c.1166G>A)?

AlphaMissense predicts likely benign (score 0.0743) — an in-silico prediction, not a clinical call.

SRCAP p.Arg389His

c.1166G>A · rs775539408 · VCV2158242

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0743 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0743	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.72, phastCons 0.001
Regional constraint	o/e 0.95	unconstrained · MANE · 2,095 bp · p 0.41 · regional, not allelic
Overall
CADD	12.58	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 0.0307% African / African-American · 23/75,002 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00285% 46/1,614,102 alleles · ultra-rare exomes 32/1,461,892 · genomes 14/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,261
South Asian	0.00769%	13,011
Admixed American	0.005%	20,003
East Asian	0.00446%	22,442
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	0.000847%	118,003

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.Arg389His
Coding: c.1166G>A
MANE Select: NM_006662
dbSNP: rs775539408
Type: single nucleotide variant
Location: chr16:30710785 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 389: the 'disordered' region

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.Arg389Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
SRCAP p.Arg389= Likely benign ★ same residue
SRCAP p.Arg389Ser 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-arg389his (accessed [today's date]).

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