Is CSF3R p.Ala208Val (c.623C>T) pathogenic?

CSF3R p.Ala208Val (c.623C>T) is classified Uncertain significance in CSF3R (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). AlphaMissense: likely benign (0.0853); Ultra-rare (popmax 0.0165%, mid); Associated with autosomal recessive severe congenital neutropenia due to CSF3R deficiency.

What condition is associated with CSF3R p.Ala208Val (c.623C>T)?

CSF3R p.Ala208Val (c.623C>T) is associated with autosomal recessive severe congenital neutropenia due to CSF3R deficiency (ClinVar).

How common is CSF3R p.Ala208Val (c.623C>T) in the general population?

CSF3R p.Ala208Val (c.623C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CSF3R p.Ala208Val (c.623C>T)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

CSF3R p.Ala208Val

Q: How is Autosomal recessive severe congenital neutropenia due to CSF3R deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.623C>T · rs372288734 · VCV960570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive severe congenital neutropenia due to CSF3R deficiency

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -7.14	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 0.34	GERP -2.4
Regional constraint	o/e 0.84	unconstrained · MANE · 13 kb · p 3.4e-07 · regional, not allelic
Overall
CADD	10.3	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 0.0165% Middle Eastern · 1/6,068 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00328% 53/1,613,824 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,068
East Asian	0.00446%	22,446
European (non-Finnish)	0.00407%	24,584
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,094

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: CSF3R
Protein: p.Ala208Val
Coding: c.623C>T
MANE Select: NM_000760
dbSNP: rs372288734
Type: single nucleotide variant
Location: chr1:36473485 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 1 PDB
Residue 208: a disulfide bond; the fibronectin type-iii 1 domain

Full CSF3R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive severe congenital neutropenia due to CSF3R deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive severe congenital neutropenia due to CSF3R deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CSF3R p.Ala208Glu Uncertain significance ★ ⚠ same residue
CSF3R p.Ala208Thr Uncertain significance ★ ⚠ same residue
CSF3R p.Ala208= Uncertain significance ★ same residue
CSF3R c.1072-1G>A Pathogenic/Likely pathogenic ★★ same condition
CSF3R c.843+2T>C Pathogenic/Likely pathogenic ★★ same condition
CSF3R c.998-2A>T Likely pathogenic ★★ same condition
CSF3R p.Arg308Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
CSF3R p.Arg440Ter Pathogenic ★★ same condition

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/csf3r-p-ala208val (accessed [today's date]).

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