Is CFH p.Arg83Ser (c.249G>T) pathogenic?

CFH p.Arg83Ser (c.249G>T) is classified Likely pathogenic in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-17). AlphaMissense: likely pathogenic (0.8401); Ultra-rare (popmax 0.0165%, mid); Associated with complement factor H deficiency.

What condition is associated with CFH p.Arg83Ser (c.249G>T)?

CFH p.Arg83Ser (c.249G>T) is associated with complement factor H deficiency (ClinVar).

How common is CFH p.Arg83Ser (c.249G>T) in the general population?

CFH p.Arg83Ser (c.249G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Immunodeficiency with factor H anomaly inherited?

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

What do computational predictors say about CFH p.Arg83Ser (c.249G>T)?

AlphaMissense predicts likely pathogenic (score 0.8401) — an in-silico prediction, not a clinical call.

CFH p.Arg83Ser

c.249G>T · VCV4291551

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8401 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

complement factor H deficiency

Computational evidence

Protein change
AlphaMissense	0.8401	likely pathogenic ✓ concordant with ClinVar
REVEL	0.635	indeterminate
SaProt	LLR -10.53	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.91	GERP -3.2, phastCons 0.24
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.84 · regional, not allelic
Overall
CADD	16.88	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 0.0165% Middle Eastern · 1/6,076 alleles

Overall 6.22e-05% 1/1,608,600 alleles · ultra-rare exomes 1/1,457,372 · genomes 0/151,228 · joint denominator

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: CFH
Protein: p.Arg83Ser
Coding: c.249G>T
MANE Select: NM_000186
Type: single nucleotide variant
Location: chr1:196673861 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 83: the sushi 2 domain

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

Disease context

complement factor H deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency with factor H anomaly (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive

Similar variants

CFH p.Arg83Met Uncertain significance ★ ⚠ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.2236+1G>C Likely pathogenic ★★ same condition
CFH p.Arg1215Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg232Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg53Cys Pathogenic/Likely pathogenic ★★ same condition
CFH p.Cys431Ser Likely pathogenic ★★ same condition
CFH p.Cys611Ter Pathogenic/Likely 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/cfh-p-arg83ser (accessed [today's date]).

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