Is CYCS p.Ser48Pro (c.142T>C) pathogenic?

CYCS p.Ser48Pro (c.142T>C) is classified Uncertain significance in CYCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely benign (0.2872); Very rare (popmax 0.000678%, nfe).

How common is CYCS p.Ser48Pro (c.142T>C) in the general population?

CYCS p.Ser48Pro (c.142T>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about CYCS p.Ser48Pro (c.142T>C)?

AlphaMissense predicts likely benign (score 0.2872) — an in-silico prediction, not a clinical call.

CYCS p.Ser48Pro

c.142T>C · rs11548783 · VCV1941675

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2872 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2872	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -9.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP -3, phastCons 0.99
Regional constraint	o/e 0.69	unconstrained · MANE · 415 bp · p 0.00062 · regional, not allelic
Overall
CADD	19.5	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 0.000678% European (non-Finnish) · 8/1,180,048 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,062 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: CYCS
Protein: p.Ser48Pro
Coding: c.142T>C
MANE Select: NM_018947
dbSNP: rs11548783
Type: single nucleotide variant
Location: chr7:25123978 (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-ser48pro (accessed [today's date]).

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