Is SRCAP p.Pro278Ala (c.832C>G) pathogenic?

SRCAP p.Pro278Ala (c.832C>G) is classified Uncertain significance in SRCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). AlphaMissense: likely benign (0.0511); Ultra-rare (popmax 0.0201%, eas).

How common is SRCAP p.Pro278Ala (c.832C>G) in the general population?

SRCAP p.Pro278Ala (c.832C>G) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about SRCAP p.Pro278Ala (c.832C>G)?

AlphaMissense predicts likely benign (score 0.0511) — an in-silico prediction, not a clinical call.

SRCAP p.Pro278Ala

c.832C>G · rs773727840 · VCV1373584

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0511 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0511	likely benign
REVEL	0.192	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 -0.35	GERP -4.4
Regional constraint	o/e 1.03	unconstrained · MANE · 217 bp · p 0.87 · regional, not allelic
Overall
CADD	8.438	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 0.0201% East Asian · 9/44,884 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00112% 18/1,614,182 alleles · ultra-rare exomes 18/1,461,892 · genomes 0/152,290 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,987
African / African-American	0.00266%	37,526
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	0.000508%	196,672

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.Pro278Ala
Coding: c.832C>G
MANE Select: NM_006662
dbSNP: rs773727840
Type: single nucleotide variant
Location: chr16:30709711 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 278: the 'disordered' region

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

Similar variants

SRCAP p.Pro278Thr Uncertain significance ★★ ⚠ same residue
SRCAP p.Pro278Arg Likely benign ★★ same residue
SRCAP p.Pro278= Likely benign ★ same residue
SRCAP p.Pro278fs Pathogenic ★ same residue
SRCAP p.Arg2329Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2435Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2444Ter Pathogenic ★★ same type
SRCAP p.Arg2718Ter Pathogenic/Likely pathogenic ★★ same type

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-pro278ala (accessed [today's date]).

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