Is CACTIN p.Arg304Trp (c.910C>T) pathogenic?

CACTIN p.Arg304Trp (c.910C>T) is classified Uncertain significance in CACTIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). AlphaMissense: likely pathogenic (0.9893); Very rare (popmax 0.00017%, nfe).

How common is CACTIN p.Arg304Trp (c.910C>T) in the general population?

CACTIN p.Arg304Trp (c.910C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CACTIN p.Arg304Trp (c.910C>T)?

AlphaMissense predicts likely pathogenic (score 0.9893) — an in-silico prediction, not a clinical call.

CACTIN p.Arg304Trp

c.910C>T · VCV3826796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9893	likely pathogenic
REVEL	0.62	indeterminate
SaProt	LLR -18.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP -2, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 10 kb · p 2.8e-11 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00017% European (non-Finnish) · 2/1,179,774 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,022 alleles · very rare

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.Arg304Trp
Coding: c.910C>T
MANE Select: NM_001080543
Type: single nucleotide variant
Location: chr19:3619217 (GRCh38)
Gene constraint: LOEUF 0.465 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.52 · 6 PDB

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-arg304trp (accessed [today's date]).

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