Is CACTIN p.Arg50Trp (c.148C>T) pathogenic?

CACTIN p.Arg50Trp (c.148C>T) is classified Uncertain significance in CACTIN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely benign (0.1185); Ultra-rare (popmax 0.0103%, nfe).

How common is CACTIN p.Arg50Trp (c.148C>T) in the general population?

CACTIN p.Arg50Trp (c.148C>T) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about CACTIN p.Arg50Trp (c.148C>T)?

AlphaMissense predicts likely benign (score 0.1185) — an in-silico prediction, not a clinical call.

CACTIN p.Arg50Trp

c.148C>T · VCV3484226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1185 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1185	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Constraint at this position
Conservation	phyloP 4.4	GERP -3.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 2,909 bp · p 0.27 · regional, not allelic
Overall
CADD	23.4	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0103% European (non-Finnish) · 117/1,137,086 alleles

Filtering AF 0.00874% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00817%

Overall 0.00788% 119/1,510,528 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,719
Remaining individualsnot grpmax-eligible	0.00344%	29,048

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: CACTIN
Protein: p.Arg50Trp
Coding: c.148C>T
MANE Select: NM_001080543
Type: single nucleotide variant
Location: chr19:3626615 (GRCh38)
Gene constraint: LOEUF 0.465 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.52 · 6 PDB
Residue 50: the 'disordered' region

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

Similar variants

CACTIN p.Ala100Ser Uncertain significance ★ ⚠ same type
CACTIN p.Ala119Val Uncertain significance ★ ⚠ same type
CACTIN p.Ala130Ser Uncertain significance ★ ⚠ same type
CACTIN p.Ala131Val Uncertain significance ★ ⚠ same type
CACTIN p.Ala317Thr Uncertain significance ★ ⚠ same type
CACTIN p.Ala427Thr Uncertain significance ★ ⚠ same type
CACTIN p.Ala500Val Uncertain significance ★ ⚠ same type
CACTIN p.Arg102Gln 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/cactin-p-arg50trp (accessed [today's date]).

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