Is TNC p.Pro1610Ser (c.4828C>T) pathogenic?

TNC p.Pro1610Ser (c.4828C>T) is classified Uncertain significance in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). AlphaMissense: likely benign (0.2264); Ultra-rare (popmax 0.0294%, afr).

How common is TNC p.Pro1610Ser (c.4828C>T) in the general population?

TNC p.Pro1610Ser (c.4828C>T) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

What do computational predictors say about TNC p.Pro1610Ser (c.4828C>T)?

AlphaMissense predicts likely benign (score 0.2264) — an in-silico prediction, not a clinical call.

TNC p.Pro1610Ser

c.4828C>T · rs371529724 · VCV2564327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2264 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2264	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	26.2	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 0.0294% African / African-American · 22/74,892 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00229% 37/1,613,876 alleles · ultra-rare exomes 23/1,461,710 · genomes 14/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,404
Admixed American	0.025%	3,999

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: TNC
Protein: p.Pro1610Ser
Coding: c.4828C>T
MANE Select: NM_002160
dbSNP: rs371529724
Type: single nucleotide variant
Location: chr9:115048284 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 1610: the fibronectin type-iii 11 domain

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

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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/tnc-p-pro1610ser (accessed [today's date]).

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