Is C8A p.Arg107Cys (c.319C>T) pathogenic?

C8A p.Arg107Cys (c.319C>T) is classified Uncertain significance in C8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-30). AlphaMissense: likely pathogenic (0.7648); Rare (popmax 0.167%, mid).

How common is C8A p.Arg107Cys (c.319C>T) in the general population?

C8A p.Arg107Cys (c.319C>T) is rare (popmax 0.167%, mid) (gnomAD).

What do computational predictors say about C8A p.Arg107Cys (c.319C>T)?

AlphaMissense predicts likely pathogenic (score 0.7648) — an in-silico prediction, not a clinical call.

C8A p.Arg107Cys

c.319C>T · rs139141074 · VCV1056494

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7648 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.167%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7648	likely pathogenic
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -12.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 2.3, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.167% Middle Eastern · 10/5,992 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.0313% 505/1,613,396 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.167%	599
African / African-American	0.149%	670
Remaining individualsnot grpmax-eligible	0.0752%	1,329
Admixed American	0.06%	1,666
European (non-Finnish)	0.0249%	4,013
East Asian	0.00447%	22,371
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,576
South Asian	0.0033%	30,331

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: C8A
Protein: p.Arg107Cys
Coding: c.319C>T
MANE Select: NM_000562
dbSNP: rs139141074
Type: single nucleotide variant
Location: chr1:56876064 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 107: a disulfide bond; the ldl-receptor class a domain

Full C8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C8A p.Arg107His Uncertain significance ★ ⚠ same residue
C8A p.Arg424Ter Pathogenic ★★ same type
C8A p.Arg498Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Glu466Ter Pathogenic ★★ same type
C8A p.Tyr210Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Tyr384Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Arg196His Uncertain significance ★★ ⚠ same type
C8A p.Arg207Gln 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/c8a-p-arg107cys (accessed [today's date]).

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