Is CACTIN p.Arg608Trp (c.1822C>T) pathogenic?

CACTIN p.Arg608Trp (c.1822C>T) is classified Uncertain significance in CACTIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). AlphaMissense: ambiguous (0.4401); Rare (popmax 0.145%, afr).

How common is CACTIN p.Arg608Trp (c.1822C>T) in the general population?

CACTIN p.Arg608Trp (c.1822C>T) is rare (popmax 0.145%, afr) (gnomAD).

What do computational predictors say about CACTIN p.Arg608Trp (c.1822C>T)?

AlphaMissense predicts ambiguous (score 0.4401) — an in-silico prediction, not a clinical call.

CACTIN p.Arg608Trp

c.1822C>T · VCV3826789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4401 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.145%, afr)

Computational evidence

Protein change
AlphaMissense	0.4401	ambiguous
REVEL	0.385	indeterminate
SaProt	LLR -11.62	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.26, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,214 bp · p 0.84 · regional, not allelic
Overall
CADD	26.6	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 0.145% African / African-American · 109/75,022 alleles

Filtering AF 0.123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.115%

Overall 0.00779% 125/1,605,006 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.145%	688
Admixed American	0.00835%	11,972
Remaining individualsnot grpmax-eligible	0.00803%	12,453
East Asian	0.00223%	44,776
European (non-Finnish)	0.000425%	235,467

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.Arg608Trp
Coding: c.1822C>T
MANE Select: NM_001080543
Type: single nucleotide variant
Location: chr19:3612378 (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-arg608trp (accessed [today's date]).

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