Is COL2A1 p.Leu715Phe (c.2143C>T) pathogenic?

COL2A1 p.Leu715Phe (c.2143C>T) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-28). AlphaMissense: likely benign (0.1856); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL2A1 p.Leu715Phe (c.2143C>T)?

COL2A1 p.Leu715Phe (c.2143C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL2A1 p.Leu715Phe (c.2143C>T) in the general population?

COL2A1 p.Leu715Phe (c.2143C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about COL2A1 p.Leu715Phe (c.2143C>T)?

AlphaMissense predicts likely benign (score 0.1856) — an in-silico prediction, not a clinical call.

COL2A1 p.Leu715Phe

c.2143C>T · rs1482498887 · VCV502044

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1856	likely benign
REVEL	0.647	pathogenic-leaning
SaProt	LLR -8.00	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	23.8	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 0.00534% African / African-American · 4/74,920 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000372% 6/1,613,146 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,730
European (non-Finnish)	0.00017%	589,953

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: COL2A1
Protein: p.Leu715Phe
Coding: c.2143C>T
MANE Select: NM_001844
dbSNP: rs1482498887
Type: single nucleotide variant
Location: chr12:47982898 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 715: the 'disordered' region; the 'triple-helical region' region

Full COL2A1 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

COL2A1 p.Cys52Ter Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Gln39Ter Pathogenic ★★ same condition
COL2A1 p.Gly546Ser Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Gly930Asp Likely pathogenic ★★ same condition
COL2A1 p.Ala1093Val Uncertain significance ★★ ⚠ same condition
COL2A1 p.Ala180Thr Uncertain significance ★★ ⚠ same condition
COL2A1 p.Ala559Ser Uncertain significance ★★ ⚠ same condition
COL2A1 p.Ala733Gly 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/col2a1-p-leu715phe (accessed [today's date]).

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