Is C1S p.Ile59Thr (c.176T>C) pathogenic?

C1S p.Ile59Thr (c.176T>C) is classified Uncertain significance in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-05). AlphaMissense: ambiguous (0.4021); Ultra-rare (popmax 0.0187%, sas).

How common is C1S p.Ile59Thr (c.176T>C) in the general population?

C1S p.Ile59Thr (c.176T>C) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about C1S p.Ile59Thr (c.176T>C)?

AlphaMissense predicts ambiguous (score 0.4021) — an in-silico prediction, not a clinical call.

C1S p.Ile59Thr

c.176T>C · rs781834878 · VCV3003284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Computational evidence

Protein change
AlphaMissense	0.4021	ambiguous
REVEL	0.395	indeterminate
SaProt	LLR -7.74	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.8, phastCons 0.98
Regional constraint	o/e 0.98	unconstrained · MANE · 4,638 bp · p 0.66 · regional, not allelic
Overall
CADD	26.6	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 0.0187% South Asian · 17/91,070 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00144% 21/1,461,852 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,357
European (non-Finnish)	0.000339%	295,005

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: C1S
Protein: p.Ile59Thr
Coding: c.176T>C
MANE Select: NM_001734
dbSNP: rs781834878
Type: single nucleotide variant
Location: chr12:7062645 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 59: the cub 1 domain

Full C1S gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1S p.Arg523Ter Pathogenic ★★ same type
C1S c.1196-3C>T Uncertain significance ★★ same type
C1S c.717+5G>A Uncertain significance ★★ same type
C1S c.717+6T>A Uncertain significance ★★ same type
C1S p.Ala227Val Uncertain significance ★★ ⚠ same type
C1S p.Ala231Val Uncertain significance ★★ ⚠ same type
C1S p.Ala584Val Uncertain significance ★★ ⚠ same type
C1S p.Ala649Thr Uncertain significance ★★ ⚠ 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/c1s-p-ile59thr (accessed [today's date]).

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