Is CFI p.Tyr65His (c.193T>C) pathogenic?

CFI p.Tyr65His (c.193T>C) is classified Uncertain significance in CFI (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-07-07). AlphaMissense: ambiguous (0.4165); Ultra-rare (popmax 0.0461%, sas); Associated with age related macular degeneration 13.

What condition is associated with CFI p.Tyr65His (c.193T>C)?

CFI p.Tyr65His (c.193T>C) is associated with age related macular degeneration 13, complement factor I deficiency, atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI p.Tyr65His (c.193T>C) in the general population?

CFI p.Tyr65His (c.193T>C) is ultra-rare (popmax 0.0461%, sas) (gnomAD).

What do computational predictors say about CFI p.Tyr65His (c.193T>C)?

AlphaMissense predicts ambiguous (score 0.4165) — an in-silico prediction, not a clinical call.

CFI p.Tyr65His

c.193T>C · rs774783110 · VCV1481515

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.4165 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, sas)

Conditions

age related macular degeneration 13

Computational evidence

Protein change
AlphaMissense	0.4165	ambiguous
REVEL	0.613	indeterminate
SaProt	LLR -5.91	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	26.0	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 0.0461% South Asian · 42/91,090 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00297% 48/1,614,104 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0461%	2,169
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Finnishnot grpmax-eligible	0.00156%	64,040
African / African-American	0.00133%	74,950

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: CFI
Protein: p.Tyr65His
Coding: c.193T>C
MANE Select: NM_000204
dbSNP: rs774783110
Type: single nucleotide variant
Location: chr4:109766689 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 65: a disulfide bond; the kazal-like domain; an α-helix

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

Disease context

Also linked: complement factor I deficiency atypical hemolytic-uremic syndrome with I factor anomaly atypical hemolytic-uremic syndrome

Similar variants

CFI c.1429+1G>C Pathogenic/Likely pathogenic ★★ same condition
CFI c.57+1G>C Likely pathogenic ★★ same condition
CFI c.658+1G>A Likely pathogenic ★★ same condition
CFI c.905-1G>C Likely pathogenic ★★ same condition
CFI p.Ala258Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CFI p.Arg187Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Arg474Ter Pathogenic/Likely pathogenic ★★ same condition
CFI c.773-3C>T Uncertain significance ★★ 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/cfi-p-tyr65his (accessed [today's date]).

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