Is CRLF1 p.Pro261Ser (c.781C>T) pathogenic?

CRLF1 p.Pro261Ser (c.781C>T) is classified Uncertain significance in CRLF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: likely benign (0.2256); Ultra-rare (popmax 0.015%, amr).

How common is CRLF1 p.Pro261Ser (c.781C>T) in the general population?

CRLF1 p.Pro261Ser (c.781C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about CRLF1 p.Pro261Ser (c.781C>T)?

AlphaMissense predicts likely benign (score 0.2256) — an in-silico prediction, not a clinical call.

CRLF1 p.Pro261Ser

c.781C>T · rs766431820 · VCV2051470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2256 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2256	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -8.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.24 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.015% Admixed American · 9/60,004 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.000991% 16/1,613,914 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,667
African / African-American	0.00668%	14,981
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	8.47e-05%	1,180,038

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.Pro261Ser
Coding: c.781C>T
MANE Select: NM_004750
dbSNP: rs766431820
Type: single nucleotide variant
Location: chr19:18596966 (GRCh38)
Gene constraint: LOEUF 1.045 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.15 · 1 PDB
Residue 261: the fibronectin type-iii 2 domain

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-pro261ser (accessed [today's date]).

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