Is CYTH3 p.Lys42Arg (c.125A>G) pathogenic?

CYTH3 p.Lys42Arg (c.125A>G) is classified Uncertain significance in CYTH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1446); Ultra-rare (popmax 0.0227%, afr).

How common is CYTH3 p.Lys42Arg (c.125A>G) in the general population?

CYTH3 p.Lys42Arg (c.125A>G) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about CYTH3 p.Lys42Arg (c.125A>G)?

AlphaMissense predicts likely benign (score 0.1446) — an in-silico prediction, not a clinical call.

CYTH3 p.Lys42Arg

c.125A>G · rs776737393 · VCV2598654

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1446 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1446	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -9.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 4.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 95 kb · p 0.75 · regional, not allelic
Overall
CADD	24.9	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 0.0227% African / African-American · 17/75,054 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00124% 20/1,614,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,415
Admixed American	0.00333%	30,013
European (non-Finnish)	8.47e-05%	1,179,979

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: CYTH3
Protein: p.Lys42Arg
Coding: c.125A>G
MANE Select: NM_004227
dbSNP: rs776737393
Type: single nucleotide variant
Location: chr7:6187714 (GRCh38)
Gene constraint: LOEUF 0.551 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 84.72 · 3 PDB

Full CYTH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYTH3 p.Lys42Gln Uncertain significance ★ ⚠ same residue
CYTH3 p.Ala389Val Uncertain significance ★ ⚠ same type
CYTH3 p.Arg175Gly Uncertain significance ★ ⚠ same type
CYTH3 p.Arg223His Uncertain significance ★ ⚠ same type
CYTH3 p.Arg283Cys Uncertain significance ★ ⚠ same type
CYTH3 p.Arg284Trp Uncertain significance ★ ⚠ same type
CYTH3 p.Arg29Gln Uncertain significance ★ ⚠ same type
CYTH3 p.Arg322Gln 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/cyth3-p-lys42arg (accessed [today's date]).

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