Is COL16A1 p.Ala726Val (c.2177C>T) pathogenic?

COL16A1 p.Ala726Val (c.2177C>T) is classified Uncertain significance in COL16A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely benign (0.0917); Very rare (popmax 0.000178%, nfe).

How common is COL16A1 p.Ala726Val (c.2177C>T) in the general population?

COL16A1 p.Ala726Val (c.2177C>T) is very rare (popmax 0.000178%, nfe) (gnomAD).

What do computational predictors say about COL16A1 p.Ala726Val (c.2177C>T)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

COL16A1 p.Ala726Val

c.2177C>T · VCV3495154

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000178%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.47	indeterminate
SaProt	LLR -6.34	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Pangolin	Δ0.38	gain · loss 0.21 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 41 kb · p 0.035 · regional, not allelic
Overall
CADD	24.4	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 0.000178% European (non-Finnish) · 2/1,126,234 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000133% 2/1,509,364 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: COL16A1
Protein: p.Ala726Val
Coding: c.2177C>T
MANE Select: NM_001856
Type: single nucleotide variant
Location: chr1:31684215 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 49.60
Residue 726: the 'disordered' region; the 'nonhelical region 6 (nc6)' region

Full COL16A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL16A1 c.1258-5C>G Benign ★★ same type
COL16A1 c.982-10G>A Benign/Likely benign ★★ same type
COL16A1 p.Lys398Arg Likely benign ★★ same type
COL16A1 p.Pro903Gln Benign ★★ same type
COL16A1 p.Thr62Lys Benign ★★ same type
COL16A1 p.Ala1005Gly Uncertain significance ★ ⚠ same type
COL16A1 p.Ala1212Thr Uncertain significance ★ ⚠ same type
COL16A1 p.Ala1385Val Uncertain significance ★ ⚠ same type

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/col16a1-p-ala726val (accessed [today's date]).

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