Is CRLF1 p.Pro48Thr (c.142C>A) pathogenic?

CRLF1 p.Pro48Thr (c.142C>A) is classified Uncertain significance in CRLF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-11). AlphaMissense: ambiguous (0.5203); Ultra-rare (popmax 0.0172%, mid); Associated with Inborn genetic diseases.

What condition is associated with CRLF1 p.Pro48Thr (c.142C>A)?

CRLF1 p.Pro48Thr (c.142C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CRLF1 p.Pro48Thr (c.142C>A) in the general population?

CRLF1 p.Pro48Thr (c.142C>A) is ultra-rare (popmax 0.0172%, mid) (gnomAD).

What do computational predictors say about CRLF1 p.Pro48Thr (c.142C>A)?

AlphaMissense predicts ambiguous (score 0.5203) — an in-silico prediction, not a clinical call.

CRLF1 p.Pro48Thr

c.142C>A · VCV4006917

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5203 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5203	ambiguous
REVEL	0.75	pathogenic-leaning
SaProt	LLR -12.02	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.24 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0172% Middle Eastern · 1/5,830 alleles

Filtering AF 0.00125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00154% 24/1,561,198 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0172%	5,830
European (non-Finnish)	0.00191%	52,289
Remaining individualsnot grpmax-eligible	0.00167%	60,048

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.Pro48Thr
Coding: c.142C>A
MANE Select: NM_004750
Type: single nucleotide variant
Location: chr19:18599820 (GRCh38)
Gene constraint: LOEUF 1.045 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.15 · 1 PDB
Residue 48: the ig-like c2-type 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

Similar variants

CRLF1 p.Arg119Cys Uncertain significance ★★ ⚠ same condition
CRLF1 p.Gly158Ala Uncertain significance ★★ ⚠ same condition
CRLF1 p.Gly161Arg Uncertain significance ★★ ⚠ same condition
CRLF1 p.Gly161Trp Uncertain significance ★★ ⚠ same condition
CRLF1 p.Gly355Val Uncertain significance ★★ ⚠ same condition
CRLF1 p.Gly64Arg Uncertain significance ★★ ⚠ same condition
CRLF1 p.Ile326Val Uncertain significance ★★ ⚠ same condition
CRLF1 p.Ser281Gly Uncertain significance ★★ ⚠ 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-pro48thr (accessed [today's date]).

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