Is CRLF1 p.Pro420= (c.1260T>C) pathogenic?

CRLF1 p.Pro420= (c.1260T>C) is classified Benign/Likely benign in CRLF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-24). Very rare (popmax 0.00764%, nfe).

How common is CRLF1 p.Pro420= (c.1260T>C) in the general population?

CRLF1 p.Pro420= (c.1260T>C) is very rare (popmax 0.00764%, nfe) (gnomAD).

CRLF1 p.Pro420=

c.1260T>C · rs140937454 · VCV737860

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00764%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.4, phastCons 1
Overall
CADD	13.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00764% European (non-Finnish) · 90/1,178,408 alleles

Filtering AF 0.00632% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00585%

Overall 0.053% 853/1,609,424 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.27%	44
Remaining individualsnot grpmax-eligible	0.146%	685
European (non-Finnish)grpmax	0.00764%	13,093
African / African-American	0.00267%	37,453

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro420=
Coding: c.1260T>C
MANE Select: NM_004750
dbSNP: rs140937454
Type: single nucleotide variant
Location: chr19:18593575 (GRCh38)
Gene constraint: LOEUF 1.045 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.15 · 1 PDB
Residue 420: the 'disordered' region

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

Similar variants

CRLF1 p.Pro420Leu Uncertain significance ★ ⚠ same residue
CRLF1 c.397+1G>A Pathogenic/Likely pathogenic ★★ same type
CRLF1 p.Trp177Ter Pathogenic ★★ same type
CRLF1 p.Arg119Cys Uncertain significance ★★ ⚠ same type
CRLF1 p.Arg81His Uncertain significance ★★ ⚠ same type
CRLF1 p.Asn168Lys Uncertain significance ★★ ⚠ same type
CRLF1 p.Asp223Asn Uncertain significance ★★ ⚠ same type
CRLF1 p.Gly158Ala 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/crlf1-p-pro420 (accessed [today's date]).

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