Is SRCAP p.Thr1745Met (c.5234C>T) pathogenic?

SRCAP p.Thr1745Met (c.5234C>T) is classified Uncertain significance in SRCAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-20). AlphaMissense: likely benign (0.1161); Very rare (popmax 0.00333%, amr); Associated with SRCAP-related disorder.

What condition is associated with SRCAP p.Thr1745Met (c.5234C>T)?

SRCAP p.Thr1745Met (c.5234C>T) is associated with SRCAP-related disorder (ClinVar).

How common is SRCAP p.Thr1745Met (c.5234C>T) in the general population?

SRCAP p.Thr1745Met (c.5234C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about SRCAP p.Thr1745Met (c.5234C>T)?

AlphaMissense predicts likely benign (score 0.1161) — an in-silico prediction, not a clinical call.

SRCAP p.Thr1745Met

c.5234C>T · rs772506621 · VCV2632092

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1161 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

SRCAP-related disorder

Computational evidence

Protein change
AlphaMissense	0.1161	likely benign
REVEL	0.28	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 6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 8,776 bp · p 0.24 · regional, not allelic
Overall
CADD	21.6	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 0.00333% Admixed American · 2/60,012 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00192% 31/1,614,076 alleles · very rare exomes 28/1,461,870 · genomes 3/152,206 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0125%	8,003
Admixed Americangrpmax	0.00333%	30,006
African / African-American	0.00267%	37,462
East Asian	0.00223%	44,886
South Asian	0.0022%	45,547
European (non-Finnish)	0.00136%	73,753

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr1745Met
Coding: c.5234C>T
MANE Select: NM_006662
dbSNP: rs772506621
Type: single nucleotide variant
Location: chr16:30724658 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1745: the 'disordered' region; a UniProt-annotated variant site (in dehmba)

Full SRCAP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SRCAP-related disorder

Similar variants

SRCAP p.Thr1745= Likely benign ★ 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-thr1745met (accessed [today's date]).

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