Is C1S p.Val139Ile (c.415G>A) pathogenic?

C1S p.Val139Ile (c.415G>A) is classified Uncertain significance in C1S (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-09). AlphaMissense: likely benign (0.0754); Very rare (popmax 0.005%, amr).

How common is C1S p.Val139Ile (c.415G>A) in the general population?

C1S p.Val139Ile (c.415G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about C1S p.Val139Ile (c.415G>A)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

C1S p.Val139Ile

c.415G>A · rs782450565 · VCV1944551

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -6.85	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 1.1	GERP -0.36, phastCons 0.014
Regional constraint	o/e 0.98	unconstrained · MANE · 4,638 bp · p 0.66 · regional, not allelic
Overall
CADD	14.14	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 0.005% Admixed American · 3/60,012 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000479% 7/1,461,780 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,004
Remaining individualsnot grpmax-eligible	0.0016%	62,502
South Asian	0.0011%	91,086
European (non-Finnish)	0.00017%	589,964

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.Val139Ile
Coding: c.415G>A
MANE Select: NM_001734
dbSNP: rs782450565
Type: single nucleotide variant
Location: chr12:7064290 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 139: a disulfide bond; the egf-like; calcium-binding domain; a β-strand

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

Similar variants

C1S p.Val139Leu Uncertain significance ★ ⚠ 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
C1S p.Ala584Val 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-val139ile (accessed [today's date]).

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