Is CFH p.Pro1111Ser (c.3331C>T) pathogenic?

CFH p.Pro1111Ser (c.3331C>T) is classified Uncertain significance in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.1037); Very rare (popmax 0.00891%, eas).

How common is CFH p.Pro1111Ser (c.3331C>T) in the general population?

CFH p.Pro1111Ser (c.3331C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CFH p.Pro1111Ser (c.3331C>T)?

AlphaMissense predicts likely benign (score 0.1037) — an in-silico prediction, not a clinical call.

CFH p.Pro1111Ser

c.3331C>T · rs772573295 · VCV1346457

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1037 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1037	likely benign
REVEL	0.204	benign-leaning
SaProt	—	withheld · numbering disagrees past residue 402 · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.9	GERP -3.1
Regional constraint	o/e 0.66	unconstrained · MANE · 3,752 bp · p 4.7e-06 · regional, not allelic
Overall
CADD	1.137	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,872 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,613,938 alleles · very rare exomes 3/1,461,822 · genomes 1/152,116 · 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.Pro1111Ser
Coding: c.3331C>T
MANE Select: NM_000186
dbSNP: rs772573295
Type: single nucleotide variant
Location: chr1:196745837 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 1111: the sushi 19 domain

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

Similar variants

CFH p.Pro1111His Uncertain significance ★ ⚠ same residue
CFH p.Pro1111Leu Uncertain significance ★ ⚠ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same type
CFH c.1520-1G>A Pathogenic/Likely pathogenic ★★ same type
CFH c.2236+1G>C Likely pathogenic ★★ same type
CFH c.3493+1G>A Pathogenic/Likely pathogenic ★★ same type
CFH c.350+1G>T Pathogenic/Likely pathogenic ★★ same type
CFH c.619+1G>A Pathogenic/Likely pathogenic ★★ 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/cfh-p-pro1111ser (accessed [today's date]).

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