Is CRLF1 p.Ser259Ter (c.776C>A) pathogenic?

CRLF1 p.Ser259Ter (c.776C>A) is classified Pathogenic in CRLF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). Absent from gnomAD v4.1; Associated with Cold-induced sweating syndrome 1.

What condition is associated with CRLF1 p.Ser259Ter (c.776C>A)?

CRLF1 p.Ser259Ter (c.776C>A) is associated with Cold-induced sweating syndrome 1 (ClinVar).

How common is CRLF1 p.Ser259Ter (c.776C>A) in the general population?

CRLF1 p.Ser259Ter (c.776C>A) is absent from gnomAD v4.1 (gnomAD).

How is Cold-induced sweating syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CRLF1 p.Ser259Ter

c.776C>A · rs1199919814 · VCV1526164

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Cold-induced sweating syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 9
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Overall
CADD	48.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CRLF1
Protein: p.Ser259Ter
Coding: c.776C>A
MANE Select: NM_004750
dbSNP: rs1199919814
Type: single nucleotide variant
Location: chr19:18596971 (GRCh38)
Gene constraint: LOEUF 1.045 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.15 · 1 PDB
Residue 259: the fibronectin type-iii 2 domain

Full CRLF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cold-induced sweating syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cold-induced sweating syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult, Childhood

Similar variants

CRLF1 c.397+1G>A Pathogenic/Likely pathogenic ★★ same condition
CRLF1 p.Trp177Ter Pathogenic ★★ same condition
CRLF1 p.Arg81His Uncertain significance ★★ ⚠ same condition
CRLF1 c.1213-1G>T Likely pathogenic ★ same condition
CRLF1 c.855+2T>G Likely pathogenic ★ same condition
CRLF1 p.Arg275Pro Likely pathogenic ★ same condition
CRLF1 p.Arg312Leu Likely pathogenic ★ same condition
CRLF1 p.Trp257Ter Pathogenic ★ same condition

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/crlf1-p-ser259ter (accessed [today's date]).

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