Is CCDC141 p.Arg180Trp (c.538C>T) pathogenic?

CCDC141 p.Arg180Trp (c.538C>T) is classified Uncertain significance in CCDC141 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-08-30). Ultra-rare (popmax 0.0278%, nfe); Associated with hypogonadotropic hypogonadism.

What condition is associated with CCDC141 p.Arg180Trp (c.538C>T)?

CCDC141 p.Arg180Trp (c.538C>T) is associated with hypogonadotropic hypogonadism, hypogonadotropic hypogonadism 7 with or without anosmia (ClinVar).

How common is CCDC141 p.Arg180Trp (c.538C>T) in the general population?

CCDC141 p.Arg180Trp (c.538C>T) is ultra-rare (popmax 0.0278%, nfe) (gnomAD).

CCDC141 p.Arg180Trp

c.538C>T · rs768401425 · VCV1341699

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0278%, nfe)

Conditions

hypogonadotropic hypogonadism

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.196	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -1.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 216 kb · p 0.0073 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0278% European (non-Finnish) · 318/1,144,740 alleles

Filtering AF 0.0253% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0243%

Overall 0.022% 340/1,546,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0278%	3,600
Remaining individualsnot grpmax-eligible	0.015%	6,653
South Asian	0.00959%	10,424
Admixed American	0.00397%	25,200
Ashkenazi Jewishnot grpmax-eligible	0.00351%	28,502
African / African-American	0.00275%	36,356

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: CCDC141
Protein: p.Arg180Trp
Coding: c.538C>T
MANE Select: NM_173648
dbSNP: rs768401425
Type: single nucleotide variant
Location: chr2:178961472 (GRCh38)
Gene constraint: LOEUF 1.052 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.36

Full CCDC141 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypogonadotropic hypogonadism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypogonadotropic hypogonadism 7 with or without anosmia

Similar variants

CCDC141 p.Gln507His Likely benign ★★ same condition
CCDC141 p.Tyr556Cys Benign/Likely benign ★★ same condition
CCDC141 p.Val1457Ile Likely benign ★★ same condition
CCDC141 p.Asp767Asn Conflicting classifications of pathogenicity ★ same condition
CCDC141 p.Leu63Phe Uncertain significance ★ same condition
CCDC141 p.Pro1438Ser Uncertain significance ★ same condition
CCDC141 p.Ala1261Val Uncertain significance ★★ same type
CCDC141 p.Ala88Thr 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/ccdc141-p-arg180trp (accessed [today's date]).

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