Is C3 p.Ile625Phe (c.1873A>T) pathogenic?

C3 p.Ile625Phe (c.1873A>T) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1801); Ultra-rare (popmax 0.0194%, nfe); Associated with age related macular degeneration 9.

What condition is associated with C3 p.Ile625Phe (c.1873A>T)?

C3 p.Ile625Phe (c.1873A>T) is associated with age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly, complement component 3 deficiency (ClinVar).

How common is C3 p.Ile625Phe (c.1873A>T) in the general population?

C3 p.Ile625Phe (c.1873A>T) is ultra-rare (popmax 0.0194%, nfe) (gnomAD).

What do computational predictors say about C3 p.Ile625Phe (c.1873A>T)?

AlphaMissense predicts likely benign (score 0.1801) — an in-silico prediction, not a clinical call.

C3 p.Ile625Phe

c.1873A>T · rs144432231 · VCV330315

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1801 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0194%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 9

Computational evidence

Protein change
AlphaMissense	0.1801	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -5.94	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 4	GERP 0.86, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	23.6	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 0.0194% European (non-Finnish) · 229/1,180,010 alleles

Filtering AF 0.0173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0165%

Overall 0.0253% 408/1,613,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.243%	412
Remaining individualsnot grpmax-eligible	0.032%	3,124
European (non-Finnish)grpmax	0.0194%	5,153
Middle Eastern	0.0164%	6,084
African / African-American	0.00267%	37,454
Admixed American	0.00167%	60,004

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: C3
Protein: p.Ile625Phe
Coding: c.1873A>T
MANE Select: NM_000064
dbSNP: rs144432231
Type: single nucleotide variant
Location: chr19:6707902 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 625: a disulfide bond

Full C3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: atypical hemolytic-uremic syndrome with C3 anomaly complement component 3 deficiency

Similar variants

C3 p.Ile625= Likely benign ★★ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same condition
C3 c.2863+1G>T Likely pathogenic ★★ same condition
C3 c.4030-2A>G Likely pathogenic ★★ same condition
C3 p.Arg161Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Arg592Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Arg592Trp Likely pathogenic ★★ ⚠ same condition
C3 p.Arg764Ter 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/c3-p-ile625phe (accessed [today's date]).

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