Is CSF1 p.Leu425Val (c.1273C>G) pathogenic?

CSF1 p.Leu425Val (c.1273C>G) is classified Uncertain significance in CSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: likely benign (0.0824); Very rare (popmax 8.48e-05%, nfe).

How common is CSF1 p.Leu425Val (c.1273C>G) in the general population?

CSF1 p.Leu425Val (c.1273C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CSF1 p.Leu425Val (c.1273C>G)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

CSF1 p.Leu425Val

c.1273C>G · VCV4007301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -6.28	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 1.6, phastCons 0.33
Regional constraint	o/e 1.00	unconstrained · MANE · 7,862 bp · p 0.92 · regional, not allelic
Overall
CADD	14.55	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 8.48e-05% European (non-Finnish) · 1/1,179,940 alleles

Overall 6.84e-05% 1/1,461,754 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: CSF1
Protein: p.Leu425Val
Coding: c.1273C>G
MANE Select: NM_000757
Type: single nucleotide variant
Location: chr1:109923894 (GRCh38)
Gene constraint: LOEUF 0.338 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.62 · 8 PDB
Residue 425: the 'disordered' region; the 'o-glycosylated at one site' region

Full CSF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSF1 p.Ala511= Benign ★★ same type
CSF1 p.Glu292= Benign ★★ same type
CSF1 p.Ala286Asp Uncertain significance ★ ⚠ same type
CSF1 p.Ala3Thr Uncertain significance ★ ⚠ same type
CSF1 p.Ala460Glu Uncertain significance ★ ⚠ same type
CSF1 p.Arg252Trp Uncertain significance ★ ⚠ same type
CSF1 p.Arg374Met Uncertain significance ★ ⚠ same type
CSF1 p.Arg449Gln 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/csf1-p-leu425val (accessed [today's date]).

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