Is CYTH4 p.Arg218Cys (c.652C>T) pathogenic?

CYTH4 p.Arg218Cys (c.652C>T) is classified Uncertain significance in CYTH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-21). AlphaMissense: likely benign (0.1801); Ultra-rare (popmax 0.011%, sas).

How common is CYTH4 p.Arg218Cys (c.652C>T) in the general population?

CYTH4 p.Arg218Cys (c.652C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about CYTH4 p.Arg218Cys (c.652C>T)?

AlphaMissense predicts likely benign (score 0.1801) — an in-silico prediction, not a clinical call.

CYTH4 p.Arg218Cys

c.652C>T · rs371162850 · VCV2384146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1801 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1801	likely benign
REVEL	0.413	indeterminate
SaProt	LLR -12.98	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.82, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 31 kb · p 5.9e-07 · regional, not allelic
Overall
CADD	28.5	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 0.011% South Asian · 10/91,090 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00198% 32/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,109
Admixed American	0.00667%	14,997
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.00136%	73,750

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: CYTH4
Protein: p.Arg218Cys
Coding: c.652C>T
MANE Select: NM_013385
dbSNP: rs371162850
Type: single nucleotide variant
Location: chr22:37303358 (GRCh38)
Gene constraint: LOEUF 0.516 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 87.17
Residue 218: the sec7 domain

Full CYTH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYTH4 p.Arg218His Uncertain significance ★ ⚠ same residue
CYTH4 p.Asn107His Benign ★★ ⚠ same type
CYTH4 p.Leu88= Benign ★★ same type
CYTH4 p.Met74Val Benign ★★ ⚠ same type
CYTH4 p.Ala136Thr Uncertain significance ★ ⚠ same type
CYTH4 p.Ala166Val Uncertain significance ★ ⚠ same type
CYTH4 p.Ala9Glu Uncertain significance ★ ⚠ same type
CYTH4 p.Arg205Gln 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/cyth4-p-arg218cys (accessed [today's date]).

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