Is CRLF3 p.Pro241Ser (c.721C>T) pathogenic?

CRLF3 p.Pro241Ser (c.721C>T) is classified Uncertain significance in CRLF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: ambiguous (0.4758); Very rare (popmax 0.000169%, nfe).

How common is CRLF3 p.Pro241Ser (c.721C>T) in the general population?

CRLF3 p.Pro241Ser (c.721C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CRLF3 p.Pro241Ser (c.721C>T)?

AlphaMissense predicts ambiguous (score 0.4758) — an in-silico prediction, not a clinical call.

CRLF3 p.Pro241Ser

c.721C>T · VCV4006923

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4758 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4758	ambiguous
REVEL	0.254	benign-leaning
SaProt	LLR -7.46	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 40 kb · p 0.056 · regional, not allelic
Overall
CADD	23.0	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 0.000169% European (non-Finnish) · 2/1,179,966 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,860 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: CRLF3
Protein: p.Pro241Ser
Coding: c.721C>T
MANE Select: NM_015986
Type: single nucleotide variant
Location: chr17:30793555 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.15
Residue 241: the fibronectin type-iii domain

Full CRLF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRLF3 p.Ala308Ser Uncertain significance ★ ⚠ same type
CRLF3 p.Ala308Thr Uncertain significance ★ ⚠ same type
CRLF3 p.Arg348Gln Uncertain significance ★ ⚠ same type
CRLF3 p.Arg38Cys Uncertain significance ★ ⚠ same type
CRLF3 p.Asn394Ser Uncertain significance ★ ⚠ same type
CRLF3 p.Asn60Lys Uncertain significance ★ ⚠ same type
CRLF3 p.Asp225Gly Uncertain significance ★ ⚠ same type
CRLF3 p.Asp240Glu 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/crlf3-p-pro241ser (accessed [today's date]).

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