Is CTRL p.Ser129Trp (c.386C>G) pathogenic?

CTRL p.Ser129Trp (c.386C>G) is classified Uncertain significance in CTRL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-17). AlphaMissense: ambiguous (0.3665); Very rare (popmax 0.00934%, afr).

How common is CTRL p.Ser129Trp (c.386C>G) in the general population?

CTRL p.Ser129Trp (c.386C>G) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about CTRL p.Ser129Trp (c.386C>G)?

AlphaMissense predicts ambiguous (score 0.3665) — an in-silico prediction, not a clinical call.

CTRL p.Ser129Trp

c.386C>G · VCV4235814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3665 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Computational evidence

Protein change
AlphaMissense	0.3665	ambiguous
REVEL	0.312	indeterminate
SaProt	LLR -11.93	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 1,915 bp · p 0.39 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,926 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000496% 8/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,704
East Asian	0.00223%	44,900

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: CTRL
Protein: p.Ser129Trp
Coding: c.386C>G
MANE Select: NM_001907
Type: single nucleotide variant
Location: chr16:67930521 (GRCh38)
Gene constraint: LOEUF 1.372 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.26
Residue 129: the peptidase s1 domain; a disulfide bond

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

Similar variants

CTRL p.Gly230Ser Uncertain significance ★★ ⚠ same type
CTRL p.Glu151Gln Benign ★★ same type
CTRL p.Val70= Benign ★★ same type
CTRL p.Ala131Thr Uncertain significance ★ ⚠ same type
CTRL p.Ala27Thr Uncertain significance ★ ⚠ same type
CTRL p.Arg136His Uncertain significance ★ ⚠ same type
CTRL p.Arg162His Uncertain significance ★ ⚠ same type
CTRL p.Arg188Trp Uncertain significance ★ ⚠ 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/ctrl-p-ser129trp (accessed [today's date]).

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