Is COL27A1 p.Phe1663Val (c.4987T>G) pathogenic?

COL27A1 p.Phe1663Val (c.4987T>G) is classified Uncertain significance in COL27A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.6488); Ultra-rare (popmax 0.0254%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL27A1 p.Phe1663Val (c.4987T>G)?

COL27A1 p.Phe1663Val (c.4987T>G) is associated with Inborn genetic diseases (ClinVar).

How common is COL27A1 p.Phe1663Val (c.4987T>G) in the general population?

COL27A1 p.Phe1663Val (c.4987T>G) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about COL27A1 p.Phe1663Val (c.4987T>G)?

AlphaMissense predicts likely pathogenic (score 0.6488) — an in-silico prediction, not a clinical call.

COL27A1 p.Phe1663Val

c.4987T>G · VCV4232168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6488 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6488	likely pathogenic
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -11.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 3.7e-08 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0254% African / African-American · 19/74,896 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00124% 20/1,613,956 alleles · ultra-rare exomes 11/1,461,834 · genomes 9/152,122 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,942
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: COL27A1
Protein: p.Phe1663Val
Coding: c.4987T>G
MANE Select: NM_032888
Type: single nucleotide variant
Location: chr9:114306568 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.13
Residue 1663: the fibrillar collagen nc1 domain

Full COL27A1 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

COL27A1 p.Ala1413Asp Uncertain significance ★★ ⚠ same condition
COL27A1 p.Ala1540Thr Uncertain significance ★★ ⚠ same condition
COL27A1 p.Ala16Val Uncertain significance ★★ same condition
COL27A1 p.Ala225Thr Uncertain significance ★★ ⚠ same condition
COL27A1 p.Ala3Thr Uncertain significance ★★ ⚠ same condition
COL27A1 p.Ala589Ser Uncertain significance ★★ ⚠ same condition
COL27A1 p.Ala650Ser Uncertain significance ★★ ⚠ same condition
COL27A1 p.Ala93Thr 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/col27a1-p-phe1663val (accessed [today's date]).

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