Is C7 p.Ser669Leu (c.2006C>T) pathogenic?

C7 p.Ser669Leu (c.2006C>T) is classified Uncertain significance in C7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-30). AlphaMissense: likely benign (0.0892); Ultra-rare (popmax 0.0396%, sas); Associated with Inborn genetic diseases.

What condition is associated with C7 p.Ser669Leu (c.2006C>T)?

C7 p.Ser669Leu (c.2006C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C7 p.Ser669Leu (c.2006C>T) in the general population?

C7 p.Ser669Leu (c.2006C>T) is ultra-rare (popmax 0.0396%, sas) (gnomAD).

What do computational predictors say about C7 p.Ser669Leu (c.2006C>T)?

AlphaMissense predicts likely benign (score 0.0892) — an in-silico prediction, not a clinical call.

C7 p.Ser669Leu

c.2006C>T · rs778220760 · VCV2377396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0892 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0396%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0892	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -9.63	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 4	GERP 2.9, phastCons 1
Overall
CADD	23.9	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 0.0396% South Asian · 36/91,014 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00254% 41/1,613,476 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0396%	2,528
Remaining individualsnot grpmax-eligible	0.00801%	12,490

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.Ser669Leu
Coding: c.2006C>T
MANE Select: NM_001565 · reported on NM_000587
dbSNP: rs778220760
Type: single nucleotide variant
Location: chr5:40972526 (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.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
C7 p.Arg372Gln 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-ser669leu (accessed [today's date]).

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