Is CYCS p.Ile58Val (c.172A>G) pathogenic?

CYCS p.Ile58Val (c.172A>G) is classified Uncertain significance in CYCS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely benign (0.1134); Ultra-rare (popmax 0.0165%, nfe).

How common is CYCS p.Ile58Val (c.172A>G) in the general population?

CYCS p.Ile58Val (c.172A>G) is ultra-rare (popmax 0.0165%, nfe) (gnomAD).

What do computational predictors say about CYCS p.Ile58Val (c.172A>G)?

AlphaMissense predicts likely benign (score 0.1134) — an in-silico prediction, not a clinical call.

CYCS p.Ile58Val

c.172A>G · rs748611135 · VCV2916203

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1134 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1134	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -8.31	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 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 415 bp · p 0.00062 · regional, not allelic
Overall
CADD	21.0	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 0.0165% European (non-Finnish) · 195/1,180,042 alleles

Filtering AF 0.0146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0139%

Overall 0.0124% 200/1,614,074 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0165%	6,052
Remaining individualsnot grpmax-eligible	0.008%	12,497

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: CYCS
Protein: p.Ile58Val
Coding: c.172A>G
MANE Select: NM_018947
dbSNP: rs748611135
Type: single nucleotide variant
Location: chr7:25123847 (GRCh38)
Gene constraint: LOEUF 0.335 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 97.95 · 13 PDB

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

Similar variants

CYCS p.Gly42Ser Likely pathogenic ★★ same type
CYCS p.Ala52Thr Uncertain significance ★★ ⚠ same type
CYCS p.Leu33Val Uncertain significance ★★ ⚠ same type
CYCS c.-6T>G Benign/Likely benign ★★ same type
CYCS p.Ala51= Likely benign ★★ same type
CYCS p.Ile59= Likely benign ★★ same type
CYCS p.Pro72= Likely benign ★★ same type
CYCS p.Ala97Asp Likely pathogenic ★ ⚠ 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/cycs-p-ile58val (accessed [today's date]).

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