Is C7 p.Val346Ile (c.1036G>A) pathogenic?

C7 p.Val346Ile (c.1036G>A) is classified Conflicting classifications of pathogenicity in C7 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-28). AlphaMissense: likely benign (0.0907); Ultra-rare (popmax 0.0394%, amr); Associated with Inborn genetic diseases.

What condition is associated with C7 p.Val346Ile (c.1036G>A)?

C7 p.Val346Ile (c.1036G>A) is associated with Inborn genetic diseases (ClinVar).

How common is C7 p.Val346Ile (c.1036G>A) in the general population?

C7 p.Val346Ile (c.1036G>A) is ultra-rare (popmax 0.0394%, amr) (gnomAD).

What do computational predictors say about C7 p.Val346Ile (c.1036G>A)?

AlphaMissense predicts likely benign (score 0.0907) — an in-silico prediction, not a clinical call.

C7 p.Val346Ile

c.1036G>A · rs369760989 · VCV2162813

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0907 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0394%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0907	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -6.41	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 -0.58	GERP -3.9
Overall
CADD	0.829	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 0.0394% Admixed American · 23/58,304 alleles

Filtering AF 0.0269% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0228%

Overall 0.00793% 127/1,601,220 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0394%	2,535
African / African-American	0.0348%	2,877
Remaining individualsnot grpmax-eligible	0.0145%	6,901
Finnishnot grpmax-eligible	0.00947%	10,565
European (non-Finnish)	0.00511%	19,556
South Asian	0.00226%	44,216
East Asian	0.00224%	44,648

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: C7
Protein: p.Val346Ile
Coding: c.1036G>A
MANE Select: NM_001565 · reported on NM_000587
dbSNP: rs369760989
Type: single nucleotide variant
Location: chr5:40949957 (GRCh38)
Structure: AlphaFold pLDDT 89.67 · 6 PDB

Full C7 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

C7 p.Val346Ala Uncertain significance ★ ⚠ same residue
C7 p.Ala359Thr Uncertain significance ★★ ⚠ same condition
C7 p.Ala53Val Uncertain significance ★★ ⚠ same condition
C7 p.Ala611Pro Uncertain significance ★★ ⚠ same condition
C7 p.Ala839Thr Uncertain significance ★★ ⚠ same condition
C7 p.Arg220Trp Uncertain significance ★★ ⚠ same condition
C7 p.Arg226Ile Uncertain significance ★★ ⚠ same condition
C7 p.Arg293Gln 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/c7-p-val346ile (accessed [today's date]).

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