Is CSF2 p.Arg21Cys (c.61C>T) pathogenic?

CSF2 p.Arg21Cys (c.61C>T) is classified Uncertain significance in CSF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely benign (0.1084); Ultra-rare (popmax 0.029%, eas).

How common is CSF2 p.Arg21Cys (c.61C>T) in the general population?

CSF2 p.Arg21Cys (c.61C>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about CSF2 p.Arg21Cys (c.61C>T)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

CSF2 p.Arg21Cys

c.61C>T · rs201688947 · VCV3077993

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -5.2
Regional constraint	o/e 0.78	unconstrained · MANE · 2,025 bp · p 0.0039 · regional, not allelic
Overall
CADD	5.802	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 0.029% East Asian · 13/44,878 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00205% 33/1,612,990 alleles · ultra-rare exomes 26/1,460,828 · genomes 7/152,162 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,452
African / African-American	0.012%	8,325
Remaining individualsnot grpmax-eligible	0.0032%	31,237
Admixed American	0.00167%	60,008
European (non-Finnish)	0.000678%	147,504

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: CSF2
Protein: p.Arg21Cys
Coding: c.61C>T
MANE Select: NM_000758
dbSNP: rs201688947
Type: single nucleotide variant
Location: chr5:132073884 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 88.30 · 11 PDB

Full CSF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSF2 p.Thr115Ile Likely benign ★★ same type
CSF2 p.Ala13Thr Uncertain significance ★ ⚠ same type
CSF2 p.Arg41His Uncertain significance ★ ⚠ same type
CSF2 p.Arg84Pro Uncertain significance ★ ⚠ same type
CSF2 p.Glu52Asp Uncertain significance ★ ⚠ same type
CSF2 p.Leu127Met Uncertain significance ★ ⚠ same type
CSF2 p.Met53Thr Uncertain significance ★ ⚠ same type
CSF2 p.Phe136Leu 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/csf2-p-arg21cys (accessed [today's date]).

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