Is C6 p.Ile434Val (c.1300A>G) pathogenic?

C6 p.Ile434Val (c.1300A>G) is classified Conflicting classifications of pathogenicity in C6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.1001); Low-frequency (popmax 2.36%, eas).

How common is C6 p.Ile434Val (c.1300A>G) in the general population?

C6 p.Ile434Val (c.1300A>G) is low-frequency (popmax 2.36%, eas) (gnomAD).

What do computational predictors say about C6 p.Ile434Val (c.1300A>G)?

AlphaMissense predicts likely benign (score 0.1001) — an in-silico prediction, not a clinical call.

C6 p.Ile434Val

c.1300A>G · rs117445335 · VCV1169629

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1001 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.36%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1001	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -5.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.021	GERP -3.8, phastCons 0.004
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	1.214	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 2.36% East Asian · 1,059/44,820 alleles

Filtering AF 2.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.2%

Overall 0.0763% 1,231/1,613,476 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	2.36%	42
Remaining individualsnot grpmax-eligible	0.197%	508
African / African-American	0.028%	3,572
South Asian	0.0187%	5,358
Admixed American	0.0133%	7,497
European (non-Finnish)	0.000254%	393,190

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: C6
Protein: p.Ile434Val
Coding: c.1300A>G
MANE Select: NM_000065
dbSNP: rs117445335
Type: single nucleotide variant
Location: chr5:41161851 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 434: an α-helix; the macpf domain

Full C6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C6 p.Ile434Thr Uncertain significance ★ ⚠ same residue
C6 p.Arg596Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Arg606Ter Pathogenic ★★ same type
C6 p.Cys218Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Tyr683Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Ala21Val Uncertain significance ★★ ⚠ same type
C6 p.Ala396Gly Uncertain significance ★★ ⚠ same type
C6 p.Ala456Thr 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/c6-p-ile434val (accessed [today's date]).

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