Is C8G p.Ala143Val (c.428C>T) pathogenic?

C8G p.Ala143Val (c.428C>T) is classified Uncertain significance in C8G (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-11). AlphaMissense: likely benign (0.1405); Ultra-rare (popmax 0.0171%, mid).

How common is C8G p.Ala143Val (c.428C>T) in the general population?

C8G p.Ala143Val (c.428C>T) is ultra-rare (popmax 0.0171%, mid) (gnomAD).

What do computational predictors say about C8G p.Ala143Val (c.428C>T)?

AlphaMissense predicts likely benign (score 0.1405) — an in-silico prediction, not a clinical call.

C8G p.Ala143Val

c.428C>T · VCV3483716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1405 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1405	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -9.39	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 0.43	GERP 0.088, phastCons 0.013
Regional constraint	o/e 1.12	unconstrained · MANE · 1,457 bp · p 0.046 · regional, not allelic
Overall
CADD	14.43	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 0.0171% Middle Eastern · 1/5,858 alleles

Filtering AF 0.00082% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000664%

Overall 0.00153% 24/1,566,744 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0171%	5,858
Ashkenazi Jewishnot grpmax-eligible	0.00376%	26,610
Finnishnot grpmax-eligible	0.00326%	30,678
South Asian	0.00236%	42,362
East Asian	0.00225%	44,366
European (non-Finnish)	0.00139%	72,157
African / African-American	0.00136%	73,586

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: C8G
Protein: p.Ala143Val
Coding: c.428C>T
MANE Select: NM_000606
Type: single nucleotide variant
Location: chr9:136946166 (GRCh38)
Gene constraint: LOEUF 1.809 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.06 · 15 PDB
Residue 143: a disulfide bond

Full C8G gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C8G p.Tyr181His Uncertain significance ★★ ⚠ same type
C8G c.276-3C>T Likely benign ★★ same type
C8G p.Arg69Gln Benign ★★ same type
C8G p.Val196Ile Likely benign ★★ same type
C8G p.Ala128Thr Uncertain significance ★ ⚠ same type
C8G p.Ala136Thr Uncertain significance ★ ⚠ same type
C8G p.Ala16Val Uncertain significance ★ ⚠ same type
C8G p.Ala190Ser 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/c8g-p-ala143val (accessed [today's date]).

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