Is C2 p.Ser50Phe (c.149C>T) pathogenic?

C2 p.Ser50Phe (c.149C>T) is classified Uncertain significance in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.1089); Very rare (popmax 0.00167%, amr); Associated with age related macular degeneration 14.

What condition is associated with C2 p.Ser50Phe (c.149C>T)?

C2 p.Ser50Phe (c.149C>T) is associated with age related macular degeneration 14, complement component 2 deficiency (ClinVar).

How common is C2 p.Ser50Phe (c.149C>T) in the general population?

C2 p.Ser50Phe (c.149C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about C2 p.Ser50Phe (c.149C>T)?

AlphaMissense predicts likely benign (score 0.1089) — an in-silico prediction, not a clinical call.

C2 p.Ser50Phe

c.149C>T · rs1277611780 · VCV904586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1089 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 14

Computational evidence

Protein change
AlphaMissense	0.1089	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -8.24	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 2.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	23.7	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,018 alleles

Overall 0.000342% 5/1,461,846 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
Admixed Americangrpmax	0.00167%	60,018
European (non-Finnish)	8.47e-05%	1,180,011

Ashkenazi Jewish 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: C2
Protein: p.Ser50Phe
Coding: c.149C>T
MANE Select: NM_000063
dbSNP: rs1277611780
Type: single nucleotide variant
Location: chr6:31928057 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 50: a disulfide bond; the sushi 1 domain; a β-strand

Full C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: complement component 2 deficiency

Similar variants

C2 c.1902+5G>A Uncertain significance ★★ same condition
C2 p.Arg129His Uncertain significance ★★ ⚠ same condition
C2 p.Arg734Leu Uncertain significance ★★ ⚠ same condition
C2 p.Asp390Ala Uncertain significance ★★ ⚠ same condition
C2 p.Asp661Asn Uncertain significance ★★ ⚠ same condition
C2 p.Lys572Asn Uncertain significance ★★ ⚠ same condition
C2 p.Phe273= Uncertain significance ★★ same condition
C2 p.Phe95Val 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/c2-p-ser50phe (accessed [today's date]).

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