Is TNC p.Arg30Trp (c.88C>T) pathogenic?

TNC p.Arg30Trp (c.88C>T) is classified Likely benign in TNC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-05). AlphaMissense: ambiguous (0.3443); Ultra-rare (popmax 0.0223%, nfe).

How common is TNC p.Arg30Trp (c.88C>T) in the general population?

TNC p.Arg30Trp (c.88C>T) is ultra-rare (popmax 0.0223%, nfe) (gnomAD).

What do computational predictors say about TNC p.Arg30Trp (c.88C>T)?

AlphaMissense predicts ambiguous (score 0.3443) — an in-silico prediction, not a clinical call.

TNC p.Arg30Trp

c.88C>T · rs149187112 · VCV719962

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3443 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3443	ambiguous
REVEL	0.521	indeterminate
SaProt	LLR -10.58	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP -1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · 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 0.0223% European (non-Finnish) · 263/1,180,024 alleles

Filtering AF 0.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0192%

Overall 0.0289% 466/1,613,956 alleles · ultra-rare exomes 435/1,461,882 · genomes 31/152,074 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.28%	358
European (non-Finnish)grpmax	0.0223%	4,487
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Admixed American	0.01%	10,000
East Asian	0.00446%	22,440
South Asian	0.00329%	30,361
African / African-American	0.00267%	37,434

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg30Trp
Coding: c.88C>T
MANE Select: NM_002160
dbSNP: rs149187112
Type: single nucleotide variant
Location: chr9:115090931 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB

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-arg30trp (accessed [today's date]).

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