Is TNC p.Arg417Cys (c.1249C>T) pathogenic?

TNC p.Arg417Cys (c.1249C>T) is classified Likely benign in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely benign (0.2025); Ultra-rare (popmax 0.0387%, nfe).

How common is TNC p.Arg417Cys (c.1249C>T) in the general population?

TNC p.Arg417Cys (c.1249C>T) is ultra-rare (popmax 0.0387%, nfe) (gnomAD).

What do computational predictors say about TNC p.Arg417Cys (c.1249C>T)?

AlphaMissense predicts likely benign (score 0.2025) — an in-silico prediction, not a clinical call.

TNC p.Arg417Cys

c.1249C>T · rs150548325 · VCV1711694

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2025 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0387%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2025	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -12.91	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	32.0	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 0.0387% European (non-Finnish) · 457/1,180,030 alleles

Filtering AF 0.0358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0346%

Overall 0.0304% 491/1,613,688 alleles · ultra-rare exomes 472/1,461,620 · genomes 19/152,068 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0387%	2,582
Remaining individualsnot grpmax-eligible	0.0336%	2,976
African / African-American	0.00801%	12,479
Admixed American	0.005%	19,998
Finnishnot grpmax-eligible	0.00471%	21,249
East Asian	0.00223%	44,876

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.Arg417Cys
Coding: c.1249C>T
MANE Select: NM_002160
dbSNP: rs150548325
Type: single nucleotide variant
Location: chr9:115086482 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 417: the egf-like 9 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-arg417cys (accessed [today's date]).

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