Is C7 p.Pro700Leu (c.2099C>T) pathogenic?

C7 p.Pro700Leu (c.2099C>T) is classified Uncertain significance in C7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-03). AlphaMissense: likely benign (0.088); Very rare (popmax 0.00682%, amr); Associated with Inborn genetic diseases.

What condition is associated with C7 p.Pro700Leu (c.2099C>T)?

C7 p.Pro700Leu (c.2099C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C7 p.Pro700Leu (c.2099C>T) in the general population?

C7 p.Pro700Leu (c.2099C>T) is very rare (popmax 0.00682%, amr) (gnomAD).

What do computational predictors say about C7 p.Pro700Leu (c.2099C>T)?

AlphaMissense predicts likely benign (score 0.088) — an in-silico prediction, not a clinical call.

C7 p.Pro700Leu

c.2099C>T · rs745729152 · VCV1386164

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.088 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00682%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.088	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2.6, phastCons 0.99
Overall
CADD	21.9	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 0.00682% Admixed American · 4/58,688 alleles

Filtering AF 0.00229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.000249% 4/1,603,528 alleles · very rare

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.Pro700Leu
Coding: c.2099C>T
MANE Select: NM_001565 · reported on NM_000587
dbSNP: rs745729152
Type: single nucleotide variant
Location: chr5:40976774 (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.Pro700Ser 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-pro700leu (accessed [today's date]).

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