Is CRLF1 p.Pro239fs (c.713dup) pathogenic?

CRLF1 p.Pro239fs (c.713dup) is classified Pathogenic in CRLF1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-22). Ultra-rare (popmax 0.04%, amr); Associated with Inborn genetic diseases.

What condition is associated with CRLF1 p.Pro239fs (c.713dup)?

CRLF1 p.Pro239fs (c.713dup) is associated with Inborn genetic diseases, Cold-induced sweating syndrome 1, cold-induced sweating syndrome (ClinVar).

How common is CRLF1 p.Pro239fs (c.713dup) in the general population?

CRLF1 p.Pro239fs (c.713dup) is ultra-rare (popmax 0.04%, amr) (gnomAD).

CRLF1 p.Pro239fs

c.713dup · rs768727082 · VCV216913

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -4.9	GERP -2.7
Overall
CADD	36.0	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

Grpmax group 0.04% Admixed American · 24/59,932 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00353% 57/1,612,466 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,497
Ashkenazi Jewishnot grpmax-eligible	0.00677%	14,764
Remaining individualsnot grpmax-eligible	0.0048%	20,816
African / African-American	0.00267%	37,484
European (non-Finnish)	0.00203%	49,143
Finnishnot grpmax-eligible	0.00158%	63,368
South Asian	0.0011%	90,976

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: CRLF1
Protein: p.Pro239fs
Coding: c.713dup
MANE Select: NM_004750
dbSNP: rs768727082
Type: Duplication
Location: chr19:18597033 (GRCh38)
Gene constraint: LOEUF 1.045 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.15 · 1 PDB
Residue 239: the fibronectin type-iii 2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cold-induced sweating syndrome 1 cold-induced sweating syndrome

Similar variants

CRLF1 p.Ser328fs Pathogenic ★★ same condition
CRLF1 p.Thr226fs Pathogenic ★ same condition
CRLF1 p.Pro239= Likely benign ★ same residue
CRLF1 p.Glu329fs Pathogenic same condition
CRLF1 c.397+1G>A Pathogenic/Likely pathogenic ★★ same condition
CRLF1 p.Gln11fs Pathogenic ★★ same condition
CRLF1 p.Pro238fs Pathogenic ★★ same condition
CRLF1 p.Trp177Ter 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-pro239fs (accessed [today's date]).

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