Is CYGB p.Pro181Ser (c.541C>T) pathogenic?

CYGB p.Pro181Ser (c.541C>T) is classified Uncertain significance in CYGB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: likely benign (0.0676); Very rare (popmax 0.00386%, amr).

How common is CYGB p.Pro181Ser (c.541C>T) in the general population?

CYGB p.Pro181Ser (c.541C>T) is very rare (popmax 0.00386%, amr) (gnomAD).

What do computational predictors say about CYGB p.Pro181Ser (c.541C>T)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

CYGB p.Pro181Ser

c.541C>T · rs757473237 · VCV3079335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00386%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -6.14	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 6.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 2,921 bp · p 6.5e-05 · regional, not allelic
Overall
CADD	21.1	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 0.00386% Admixed American · 1/25,932 alleles

Filtering AF 0.000588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00043%

Overall 0.000939% 12/1,278,000 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00386%	25,932
European (non-Finnish)	0.0011%	91,242

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: CYGB
Protein: p.Pro181Ser
Coding: c.541C>T
MANE Select: NM_134268
dbSNP: rs757473237
Type: single nucleotide variant
Location: chr17:76528610 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75 · 9 PDB
Residue 181: an α-helix

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

Similar variants

PRCD c.74+1G>A Pathogenic/Likely pathogenic ★★ same type
PRCD p.Arg18Ter Pathogenic ★★ same type
PRCD p.Arg22Ter Pathogenic ★★ same type
PRCD p.Met1Thr Pathogenic/Likely pathogenic ★★ same type
PRCD c.75-3C>G Uncertain significance ★★ same type
PRCD c.*1259G>A Uncertain significance ★★ same type
PRCD c.*1480C>G Uncertain significance ★★ same type
PRCD c.*266C>T 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/cygb-p-pro181ser (accessed [today's date]).

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