Is CSF1 p.Val135Leu (c.403G>C) pathogenic?

CSF1 p.Val135Leu (c.403G>C) is classified Uncertain significance in CSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: ambiguous (0.4847); Very rare (popmax 0.00043%, nfe).

How common is CSF1 p.Val135Leu (c.403G>C) in the general population?

CSF1 p.Val135Leu (c.403G>C) is very rare (popmax 0.00043%, nfe) (gnomAD).

What do computational predictors say about CSF1 p.Val135Leu (c.403G>C)?

AlphaMissense predicts ambiguous (score 0.4847) — an in-silico prediction, not a clinical call.

CSF1 p.Val135Leu

c.403G>C · rs377085953 · VCV3077981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00043%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4847	ambiguous
REVEL	0.189	benign-leaning
SaProt	LLR -5.86	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 2.6	GERP 0.68, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 7,862 bp · p 0.92 · regional, not allelic
Overall
CADD	19.94	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 0.00043% European (non-Finnish) · 5/1,162,502 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000315% 5/1,587,218 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.Val135Leu
Coding: c.403G>C
MANE Select: NM_000757
dbSNP: rs377085953
Type: single nucleotide variant
Location: chr1:109921853 (GRCh38)
Gene constraint: LOEUF 0.338 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.62 · 8 PDB
Residue 135: a disulfide bond; a β-strand

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-val135leu (accessed [today's date]).

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