Is C3 p.Val165Phe (c.493G>T) pathogenic?

C3 p.Val165Phe (c.493G>T) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-30). AlphaMissense: likely benign (0.209); Very rare (popmax 8.47e-05%, nfe); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with C3 p.Val165Phe (c.493G>T)?

C3 p.Val165Phe (c.493G>T) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How common is C3 p.Val165Phe (c.493G>T) in the general population?

C3 p.Val165Phe (c.493G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about C3 p.Val165Phe (c.493G>T)?

AlphaMissense predicts likely benign (score 0.209) — an in-silico prediction, not a clinical call.

C3 p.Val165Phe

c.493G>T · VCV4280267

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.209	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -13.93	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.3	GERP -3.2
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	13.83	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.2e-05% 1/1,614,168 alleles · very rare exomes 1/1,461,870 · genomes 0/152,298 · 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: C3
Protein: p.Val165Phe
Coding: c.493G>T
MANE Select: NM_000064
Type: single nucleotide variant
Location: chr19:6718105 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 165: a β-strand

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

Disease context

atypical hemolytic-uremic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

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C3 p.Ile1157Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Trp1034Arg Likely pathogenic ★★ same condition
C3 c.1269+4C>A Uncertain significance ★★ same condition
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C3 p.Ala540Ser 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/c3-p-val165phe (accessed [today's date]).

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