Is CRLF1 p.Leu74Pro (c.221T>C) pathogenic?

CRLF1 p.Leu74Pro (c.221T>C) is classified Uncertain significance in CRLF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely pathogenic (0.9002); Very rare (popmax 0.00136%, nfe).

How common is CRLF1 p.Leu74Pro (c.221T>C) in the general population?

CRLF1 p.Leu74Pro (c.221T>C) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about CRLF1 p.Leu74Pro (c.221T>C)?

AlphaMissense predicts likely pathogenic (score 0.9002) — an in-silico prediction, not a clinical call.

CRLF1 p.Leu74Pro

c.221T>C · VCV3375191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9002 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9002	likely pathogenic
REVEL	0.976	strongly pathogenic-leaning
SaProt	LLR -16.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.24 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00136% European (non-Finnish) · 16/1,175,240 alleles

Filtering AF 0.000806% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000652%

Overall 0.00106% 17/1,603,708 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00136%	73,453
African / African-American	0.00134%	74,842

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.Leu74Pro
Coding: c.221T>C
MANE Select: NM_004750
Type: single nucleotide variant
Location: chr19:18599741 (GRCh38)
Gene constraint: LOEUF 1.045 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.15 · 1 PDB
Residue 74: a disulfide bond; a UniProt-annotated variant site (in ciss1); the ig-like c2-type domain

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

Similar variants

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
CRLF1 p.Gly161Arg 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-leu74pro (accessed [today's date]).

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