Is SRCAP p.Thr2776Ile (c.8327C>T) pathogenic?

SRCAP p.Thr2776Ile (c.8327C>T) is classified Uncertain significance in SRCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-27). AlphaMissense: likely benign (0.1241); Very rare (popmax 0.00449%, eas); Associated with Inborn genetic diseases.

What condition is associated with SRCAP p.Thr2776Ile (c.8327C>T)?

SRCAP p.Thr2776Ile (c.8327C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SRCAP p.Thr2776Ile (c.8327C>T) in the general population?

SRCAP p.Thr2776Ile (c.8327C>T) is very rare (popmax 0.00449%, eas) (gnomAD).

What do computational predictors say about SRCAP p.Thr2776Ile (c.8327C>T)?

AlphaMissense predicts likely benign (score 0.1241) — an in-silico prediction, not a clinical call.

SRCAP p.Thr2776Ile

c.8327C>T · rs1382380473 · VCV2489837

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1241 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1241	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1	GERP -0.79, phastCons 0.53
Regional constraint	o/e 1.06	unconstrained · MANE · 2,598 bp · p 0.058 · regional, not allelic
Overall
CADD	14.06	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00449% East Asian · 2/44,520 alleles

Filtering AF 0.000745% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000279%

Overall 0.000256% 4/1,563,210 alleles · very rare exomes 3/1,411,028 · genomes 1/152,182 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00449%	22,260
Admixed American	0.00187%	53,584
European (non-Finnish)	8.66e-05%	1,154,830

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.Thr2776Ile
Coding: c.8327C>T
MANE Select: NM_006662
dbSNP: rs1382380473
Type: single nucleotide variant
Location: chr16:30738367 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2776: the 'disordered' region; a UniProt-annotated variant site (in dehmba); a UniProt-annotated variant site (in flhs)

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-thr2776ile (accessed [today's date]).

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