Is C1S p.Trp304Arg (c.910T>C) pathogenic?

C1S p.Trp304Arg (c.910T>C) is classified Uncertain significance in C1S (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-24). AlphaMissense: ambiguous (0.3979); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with C1S p.Trp304Arg (c.910T>C)?

C1S p.Trp304Arg (c.910T>C) is associated with Inborn genetic diseases (ClinVar).

How common is C1S p.Trp304Arg (c.910T>C) in the general population?

C1S p.Trp304Arg (c.910T>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about C1S p.Trp304Arg (c.910T>C)?

AlphaMissense predicts ambiguous (score 0.3979) — an in-silico prediction, not a clinical call.

C1S p.Trp304Arg

c.910T>C · rs199728575 · VCV1510319

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3979	ambiguous
REVEL	0.235	benign-leaning
SaProt	LLR -4.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 487 bp · p 6.7e-05 · regional, not allelic
Overall
CADD	21.2	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 0.005% Admixed American · 3/60,030 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00341% 55/1,613,818 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
Remaining individualsnot grpmax-eligible	0.0064%	15,624
Admixed Americangrpmax	0.005%	20,010
European (non-Finnish)	0.00331%	30,248
Finnishnot grpmax-eligible	0.00156%	64,042

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: C1S
Protein: p.Trp304Arg
Coding: c.910T>C
MANE Select: NM_001734
dbSNP: rs199728575
Type: single nucleotide variant
Location: chr12:7066556 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 304: a disulfide bond; the sushi 1 domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C1S p.Ala227Val Uncertain significance ★★ ⚠ same condition
C1S p.Ala231Val Uncertain significance ★★ ⚠ same condition
C1S p.Ala649Thr Uncertain significance ★★ ⚠ same condition
C1S p.Arg207Gln Uncertain significance ★★ ⚠ same condition
C1S p.Arg286Cys Uncertain significance ★★ ⚠ same condition
C1S p.Arg481Gly Uncertain significance ★★ ⚠ same condition
C1S p.Arg496Gln Uncertain significance ★★ ⚠ same condition
C1S p.Arg581Cys 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/c1s-p-trp304arg (accessed [today's date]).

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