Is SRCAP p.Thr2819Ile (c.8456C>T) pathogenic?

SRCAP p.Thr2819Ile (c.8456C>T) is classified Uncertain significance in SRCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely benign (0.0856); Very rare (popmax 0.000595%, nfe); Associated with SRCAP-related disorder.

What condition is associated with SRCAP p.Thr2819Ile (c.8456C>T)?

SRCAP p.Thr2819Ile (c.8456C>T) is associated with SRCAP-related disorder (ClinVar).

How common is SRCAP p.Thr2819Ile (c.8456C>T) in the general population?

SRCAP p.Thr2819Ile (c.8456C>T) is very rare (popmax 0.000595%, nfe) (gnomAD).

What do computational predictors say about SRCAP p.Thr2819Ile (c.8456C>T)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

SRCAP p.Thr2819Ile

c.8456C>T · rs1297031168 · VCV2635932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000595%, nfe)

Conditions

SRCAP-related disorder

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.294	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.4	GERP -0.66, phastCons 0.015
Regional constraint	o/e 1.06	unconstrained · MANE · 2,598 bp · p 0.058 · regional, not allelic
Overall
CADD	14.08	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 0.000595% European (non-Finnish) · 7/1,176,418 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000436% 7/1,607,068 alleles · very rare exomes 7/1,454,766 · genomes 0/152,302 · joint denominator

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.Thr2819Ile
Coding: c.8456C>T
MANE Select: NM_006662
dbSNP: rs1297031168
Type: single nucleotide variant
Location: chr16:30738496 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2819: 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

SRCAP-related disorder

Similar variants

SRCAP p.Thr2819Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
SRCAP p.Arg2435Ter Pathogenic/Likely pathogenic ★★ same condition
SRCAP p.Arg2444Ter Pathogenic ★★ same condition
SRCAP p.Arg2748Ter Pathogenic ★★ same condition
SRCAP p.Gln3043His Uncertain significance ★★ ⚠ same condition
SRCAP p.Gln3202His Uncertain significance ★★ same condition
SRCAP p.Leu2652Arg Uncertain significance ★★ same condition
SRCAP p.Pro1728Ala 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-thr2819ile (accessed [today's date]).

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