Is SRCAP p.Lys993Arg (c.2978A>G) pathogenic?

SRCAP p.Lys993Arg (c.2978A>G) is classified Uncertain significance in SRCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-30). AlphaMissense: ambiguous (0.5374); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with SRCAP p.Lys993Arg (c.2978A>G)?

SRCAP p.Lys993Arg (c.2978A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SRCAP p.Lys993Arg (c.2978A>G) in the general population?

SRCAP p.Lys993Arg (c.2978A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SRCAP p.Lys993Arg (c.2978A>G)?

AlphaMissense predicts ambiguous (score 0.5374) — an in-silico prediction, not a clinical call.

SRCAP p.Lys993Arg

c.2978A>G · rs2506661319 · VCV2230205

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5374 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5374	ambiguous
REVEL	0.558	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 4,608 bp · p 6.7e-06 · regional, not allelic
Overall
CADD	24.8	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 0.0165% Middle Eastern · 1/6,054 alleles

Overall 0.000124% 2/1,613,324 alleles · ultra-rare exomes 2/1,460,998 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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.Lys993Arg
Coding: c.2978A>G
MANE Select: NM_006662
dbSNP: rs2506661319
Type: single nucleotide variant
Location: chr16:30720322 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 993: 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.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
SRCAP p.Ala2945Val 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-lys993arg (accessed [today's date]).

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