Is CRLF1 p.Ile43Phe (c.127A>T) pathogenic?

CRLF1 p.Ile43Phe (c.127A>T) is classified Uncertain significance in CRLF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-20). AlphaMissense: likely pathogenic (0.8213); Very rare (popmax 0.00229%, eas).

How common is CRLF1 p.Ile43Phe (c.127A>T) in the general population?

CRLF1 p.Ile43Phe (c.127A>T) is very rare (popmax 0.00229%, eas) (gnomAD).

What do computational predictors say about CRLF1 p.Ile43Phe (c.127A>T)?

AlphaMissense predicts likely pathogenic (score 0.8213) — an in-silico prediction, not a clinical call.

CRLF1 p.Ile43Phe

c.127A>T · VCV3900430

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8213	likely pathogenic
REVEL	0.589	indeterminate
SaProt	LLR -14.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.24 · regional, not allelic
Overall
CADD	28.4	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 0.00229% East Asian · 1/43,762 alleles

Overall 7.21e-05% 1/1,387,624 alleles · very rare

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.Ile43Phe
Coding: c.127A>T
MANE Select: NM_004750
Type: single nucleotide variant
Location: chr19:18599835 (GRCh38)
Gene constraint: LOEUF 1.045 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.15 · 1 PDB
Residue 43: the ig-like c2-type domain; a β-strand

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-ile43phe (accessed [today's date]).

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