Is SRCAP p.Pro1535Ala (c.4603C>G) pathogenic?

SRCAP p.Pro1535Ala (c.4603C>G) is classified Benign/Likely benign in SRCAP (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-05-11). AlphaMissense: likely benign (0.0764); Low-frequency (popmax 2.59%, mid).

How common is SRCAP p.Pro1535Ala (c.4603C>G) in the general population?

SRCAP p.Pro1535Ala (c.4603C>G) is low-frequency (popmax 2.59%, mid) (gnomAD).

What do computational predictors say about SRCAP p.Pro1535Ala (c.4603C>G)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

SRCAP p.Pro1535Ala

c.4603C>G · rs117804715 · VCV160035

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.59%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.166	moderately 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 1.8	GERP -0.37, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 8,776 bp · p 0.24 · regional, not allelic
Overall
CADD	20.3	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 2.59% Middle Eastern · 157/6,062 alleles

Filtering AF 2.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.13%

Overall 0.759% 12,247/1,613,988 alleles · low-frequency exomes 11,240/1,461,720 · genomes 1,007/152,268 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.59%	39
Ashkenazi Jewishnot grpmax-eligible	2.3%	43
Remaining individualsnot grpmax-eligible	0.931%	107
Admixed American	0.88%	114
European (non-Finnish)	0.812%	123
South Asian	0.561%	178
African / African-American	0.163%	615
Finnishnot grpmax-eligible	0.124%	809
East Asian	0.00891%	11,223

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.Pro1535Ala
Coding: c.4603C>G
MANE Select: NM_006662
dbSNP: rs117804715
Type: single nucleotide variant
Location: chr16:30724027 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1535: a UniProt-annotated variant site (in dehmba)

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

Similar variants

SRCAP p.Pro1535Ser Uncertain significance ★ ⚠ same residue
SRCAP p.Pro1535= Likely benign ★ 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
SRCAP p.Arg2748Ter Pathogenic ★★ same type
SRCAP p.Gln2407Ter 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-pro1535ala (accessed [today's date]).

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