Is CRLF1 p.Ala58Pro (c.172G>C) pathogenic?

CRLF1 p.Ala58Pro (c.172G>C) is classified Uncertain significance in CRLF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: likely pathogenic (0.9408); Very rare (popmax 0.00135%, afr); Associated with Inborn genetic diseases.

What condition is associated with CRLF1 p.Ala58Pro (c.172G>C)?

CRLF1 p.Ala58Pro (c.172G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CRLF1 p.Ala58Pro (c.172G>C) in the general population?

CRLF1 p.Ala58Pro (c.172G>C) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about CRLF1 p.Ala58Pro (c.172G>C)?

AlphaMissense predicts likely pathogenic (score 0.9408) — an in-silico prediction, not a clinical call.

CRLF1 p.Ala58Pro

c.172G>C · VCV4006915

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9408	likely pathogenic
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.24 · regional, not allelic
Overall
CADD	28.8	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 0.00135% African / African-American · 1/74,246 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00019% 3/1,580,912 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,246
European (non-Finnish)	0.000172%	580,302

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.Ala58Pro
Coding: c.172G>C
MANE Select: NM_004750
Type: single nucleotide variant
Location: chr19:18599790 (GRCh38)
Gene constraint: LOEUF 1.045 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.15 · 1 PDB
Residue 58: the ig-like c2-type domain; a β-strand

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.Pro48Thr 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-ala58pro (accessed [today's date]).

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