Is CFH p.Arg2Thr (c.5G>C) pathogenic?

CFH p.Arg2Thr (c.5G>C) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.2045); Very rare (popmax 0.00714%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with CFH p.Arg2Thr (c.5G>C)?

CFH p.Arg2Thr (c.5G>C) is associated with inherited retinal dystrophy, complement factor H deficiency, age related macular degeneration 4 (ClinVar).

How common is CFH p.Arg2Thr (c.5G>C) in the general population?

CFH p.Arg2Thr (c.5G>C) is very rare (popmax 0.00714%, nfe) (gnomAD).

What do computational predictors say about CFH p.Arg2Thr (c.5G>C)?

AlphaMissense predicts likely benign (score 0.2045) — an in-silico prediction, not a clinical call.

CFH p.Arg2Thr

c.5G>C · rs142266551 · VCV1388423

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2045 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00714%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.2045	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -6.72	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 0.32	GERP -4.7, phastCons 0.01
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.84 · regional, not allelic
Overall
CADD	14.96	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 0.00714% European (non-Finnish) · 84/1,176,462 alleles

Filtering AF 0.00589% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00542%

Overall 0.00547% 88/1,610,014 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00714%	14,006
Remaining individualsnot grpmax-eligible	0.00321%	31,184
African / African-American	0.00267%	37,430

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.Arg2Thr
Coding: c.5G>C
MANE Select: NM_000186
dbSNP: rs142266551
Type: single nucleotide variant
Location: chr1:196652122 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: complement factor H deficiency age related macular degeneration 4 atypical hemolytic-uremic syndrome

Similar variants

CFH p.Arg2Ile Uncertain significance ★ ⚠ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.1520-1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH c.2236+1G>C Likely pathogenic ★★ same condition
CFH c.3493+1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH c.619+1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg1215Leu Likely pathogenic ★★ ⚠ same condition
CFH p.Arg1215Ter 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-arg2thr (accessed [today's date]).

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