Is CRLF1 p.Pro138Ser (c.412C>T) pathogenic?

CRLF1 p.Pro138Ser (c.412C>T) is classified Uncertain significance in CRLF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.9943); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with CRLF1 p.Pro138Ser (c.412C>T)?

CRLF1 p.Pro138Ser (c.412C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CRLF1 p.Pro138Ser (c.412C>T) in the general population?

CRLF1 p.Pro138Ser (c.412C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CRLF1 p.Pro138Ser (c.412C>T)?

AlphaMissense predicts likely pathogenic (score 0.9943) — an in-silico prediction, not a clinical call.

CRLF1 p.Pro138Ser

c.412C>T · VCV4616585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9943 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9943	likely pathogenic · top 6% in CRLF1
REVEL	0.638	indeterminate
SaProt	LLR -13.11	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 9.8	GERP 0.51, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.24 · regional, not allelic
Overall
CADD	29.7	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 0.00333% Admixed American · 2/60,016 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000616% 9/1,461,742 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,008
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000508%	196,660

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.Pro138Ser
Coding: c.412C>T
MANE Select: NM_004750
Type: single nucleotide variant
Location: chr19:18598887 (GRCh38)
Gene constraint: LOEUF 1.045 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.15 · 1 PDB
Residue 138: a UniProt-annotated variant site (in ciss1); the fibronectin type-iii 1 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.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-pro138ser (accessed [today's date]).

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