Is SRCAP p.Pro1059Leu (c.3176C>T) pathogenic?

SRCAP p.Pro1059Leu (c.3176C>T) is classified Likely benign in SRCAP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0912); Ultra-rare (popmax 0.0933%, amr); Associated with Inborn genetic diseases.

What condition is associated with SRCAP p.Pro1059Leu (c.3176C>T)?

SRCAP p.Pro1059Leu (c.3176C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SRCAP p.Pro1059Leu (c.3176C>T) in the general population?

SRCAP p.Pro1059Leu (c.3176C>T) is ultra-rare (popmax 0.0933%, amr) (gnomAD).

What do computational predictors say about SRCAP p.Pro1059Leu (c.3176C>T)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

SRCAP p.Pro1059Leu

c.3176C>T · rs201831987 · VCV725848

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0933%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.26	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 2.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 8,776 bp · p 0.24 · regional, not allelic
Overall
CADD	22.2	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 0.0933% Admixed American · 56/60,010 alleles

Filtering AF 0.0737% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0667%

Overall 0.00576% 93/1,614,096 alleles · ultra-rare exomes 75/1,461,824 · genomes 18/152,272 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0933%	1,072
Remaining individualsnot grpmax-eligible	0.0128%	7,814
African / African-American	0.00666%	15,007
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Finnishnot grpmax-eligible	0.00313%	31,995
East Asian	0.00223%	44,882
European (non-Finnish)	0.00161%	62,106
South Asian	0.0011%	91,076

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.Pro1059Leu
Coding: c.3176C>T
MANE Select: NM_006662
dbSNP: rs201831987
Type: single nucleotide variant
Location: chr16:30720901 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1059: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SRCAP p.Pro1059= Likely benign ★★ same residue
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

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-pro1059leu (accessed [today's date]).

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