Is C8A p.Arg107His (c.320G>A) pathogenic?

C8A p.Arg107His (c.320G>A) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.2486); Very rare (popmax 0.00447%, eas).

How common is C8A p.Arg107His (c.320G>A) in the general population?

C8A p.Arg107His (c.320G>A) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about C8A p.Arg107His (c.320G>A)?

AlphaMissense predicts likely benign (score 0.2486) — an in-silico prediction, not a clinical call.

C8A p.Arg107His

c.320G>A · VCV3994158

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2486 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2486	likely benign
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -10.55	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	29.3	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 0.00447% East Asian · 2/44,740 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000558% 9/1,613,446 alleles · very rare exomes 9/1,461,234 · genomes 0/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,370
Admixed American	0.00167%	59,978
Remaining individualsnot grpmax-eligible	0.0016%	62,470
Finnishnot grpmax-eligible	0.00156%	63,990
South Asian	0.0011%	91,042
European (non-Finnish)	0.000254%	393,241

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.Arg107His
Coding: c.320G>A
MANE Select: NM_000562
Type: single nucleotide variant
Location: chr1:56876065 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 107: the ldl-receptor class a domain

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

Similar variants

C8A p.Arg107Cys 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-arg107his (accessed [today's date]).

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