Is COL6A3 p.Ser599Pro (c.1795T>C) pathogenic?

COL6A3 p.Ser599Pro (c.1795T>C) is classified Uncertain significance in COL6A3 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-13). AlphaMissense: likely benign (0.0688); Very rare (popmax 0.00127%, nfe); Associated with Ullrich congenital muscular dystrophy 1C.

What condition is associated with COL6A3 p.Ser599Pro (c.1795T>C)?

COL6A3 p.Ser599Pro (c.1795T>C) is associated with Ullrich congenital muscular dystrophy 1C (ClinVar).

How common is COL6A3 p.Ser599Pro (c.1795T>C) in the general population?

COL6A3 p.Ser599Pro (c.1795T>C) is very rare (popmax 0.00127%, nfe) (gnomAD).

How is Ullrich congenital muscular dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COL6A3 p.Ser599Pro (c.1795T>C)?

AlphaMissense predicts likely benign (score 0.0688) — an in-silico prediction, not a clinical call.

COL6A3 p.Ser599Pro

c.1795T>C · rs759009773 · VCV1723776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0688 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Ullrich congenital muscular dystrophy 1C

Computational evidence

Protein change
AlphaMissense	0.0688	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.79	GERP -3.4
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.26 · regional, not allelic
Overall
CADD	0.071	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,180,028 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000929% 15/1,614,164 alleles · very rare exomes 15/1,461,884 · genomes 0/152,280 · joint denominator

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: COL6A3
Protein: p.Ser599Pro
Coding: c.1795T>C
MANE Select: NM_004369
dbSNP: rs759009773
Type: single nucleotide variant
Location: chr2:237381017 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 599: the 'nonhelical region' region; the vwfa 3 domain

Full COL6A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ullrich congenital muscular dystrophy 1C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Ullrich congenital muscular dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (United Kingdom)

Similar variants

COL6A3 c.3071-2A>G Likely pathogenic ★★ same condition
COL6A3 c.6210+1G>A Pathogenic ★★ same condition
COL6A3 c.6930+5G>A Pathogenic ★★ same condition
COL6A3 p.Arg465Ter Pathogenic ★★ same condition
COL6A3 p.Arg609Ter Pathogenic/Likely pathogenic ★★ same condition
COL6A3 p.Arg836Ter Pathogenic/Likely pathogenic ★★ same condition
COL6A3 c.709+4A>G Uncertain significance ★★ same condition
COL6A3 c.7669-3C>T 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/col6a3-p-ser599pro (accessed [today's date]).

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