Is C1S p.Pro160Leu (c.479C>T) pathogenic?

C1S p.Pro160Leu (c.479C>T) is classified Uncertain significance in C1S (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-23). AlphaMissense: likely benign (0.205); Very rare (popmax 0.00267%, afr).

How common is C1S p.Pro160Leu (c.479C>T) in the general population?

C1S p.Pro160Leu (c.479C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about C1S p.Pro160Leu (c.479C>T)?

AlphaMissense predicts likely benign (score 0.205) — an in-silico prediction, not a clinical call.

C1S p.Pro160Leu

c.479C>T · rs1400068569 · VCV1422066

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.205	likely benign
REVEL	0.445	indeterminate
SaProt	LLR -9.46	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 4,638 bp · p 0.66 · regional, not allelic
Overall
CADD	24.3	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 0.00267% African / African-American · 2/74,876 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000929% 15/1,613,922 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,438
South Asian	0.0011%	91,080
European (non-Finnish)	0.00102%	98,334

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.Pro160Leu
Coding: c.479C>T
MANE Select: NM_001734
dbSNP: rs1400068569
Type: single nucleotide variant
Location: chr12:7064354 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 160: a disulfide bond; the egf-like; calcium-binding domain

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

Similar variants

C1S p.Pro160Arg Uncertain significance ★ ⚠ same residue
C1S p.Pro160= Likely benign ★ same residue
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

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-pro160leu (accessed [today's date]).

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