Is CFHR1 p.Thr109Ile (c.326C>T) pathogenic?

CFHR1 p.Thr109Ile (c.326C>T) is classified Likely benign in CFHR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely benign (0.1113); Ultra-rare (popmax 0.0137%, afr).

How common is CFHR1 p.Thr109Ile (c.326C>T) in the general population?

CFHR1 p.Thr109Ile (c.326C>T) is ultra-rare (popmax 0.0137%, afr) (gnomAD).

What do computational predictors say about CFHR1 p.Thr109Ile (c.326C>T)?

AlphaMissense predicts likely benign (score 0.1113) — an in-silico prediction, not a clinical call.

CFHR1 p.Thr109Ile

c.326C>T · VCV4683960

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1113 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1113	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -14	GERP 0.97
Regional constraint	o/e 0.74	unconstrained · MANE · 8,251 bp · p 0.0011 · regional, not allelic
Overall
CADD	7.083	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 0.0137% African / African-American · 8/58,288 alleles

Filtering AF 0.00678% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00495%

Overall 0.00216% 33/1,524,792 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0137%	7,286
European (non-Finnish)	0.00221%	45,158

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: CFHR1
Protein: p.Thr109Ile
Coding: c.326C>T
MANE Select: NM_002113
Type: single nucleotide variant
Location: chr1:196826901 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.21 · 2 PDB
Residue 109: a disulfide bond; the sushi 2 domain

Full CFHR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR1 p.Asp218Asn Uncertain significance ★★ ⚠ same type
CFHR1 p.Gln44Ter Uncertain significance ★★ same type
CFHR1 p.Ile214Asn Uncertain significance ★★ ⚠ same type
CFHR1 p.Ile70Val Uncertain significance ★★ ⚠ same type
CFHR1 p.Pro223Leu Uncertain significance ★★ ⚠ same type
CFHR1 p.Tyr304Cys Uncertain significance ★★ ⚠ same type
CFHR1 c.253+108G>C Benign ★★ same type
CFHR1 c.253+213G>A Benign ★★ 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/cfhr1-p-thr109ile (accessed [today's date]).

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