Is TNC p.Arg438Gln (c.1313G>A) pathogenic?

TNC p.Arg438Gln (c.1313G>A) is classified Uncertain significance in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.0947); Ultra-rare (popmax 0.0214%, nfe).

How common is TNC p.Arg438Gln (c.1313G>A) in the general population?

TNC p.Arg438Gln (c.1313G>A) is ultra-rare (popmax 0.0214%, nfe) (gnomAD).

What do computational predictors say about TNC p.Arg438Gln (c.1313G>A)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

TNC p.Arg438Gln

c.1313G>A · rs763289734 · VCV2471302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	phastCons 0.79
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

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 0.0214% European (non-Finnish) · 253/1,179,936 alleles

Filtering AF 0.0193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0174% 281/1,613,632 alleles · ultra-rare exomes 275/1,461,730 · genomes 6/151,902 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0214%	4,664
Admixed American	0.0133%	7,498
Remaining individualsnot grpmax-eligible	0.0128%	7,810
South Asian	0.011%	9,107
African / African-American	0.00267%	37,403

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.Arg438Gln
Coding: c.1313G>A
MANE Select: NM_002160
dbSNP: rs763289734
Type: single nucleotide variant
Location: chr9:115086418 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 438: the egf-like 10 domain

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

Similar variants

TNC p.Arg438Trp Likely benign ★ ⚠ same residue
TNC p.Arg1127Trp Uncertain significance ★★ ⚠ same type
TNC p.Arg608Cys Uncertain significance ★★ ⚠ same type
TNC p.Arg669His Uncertain significance ★★ ⚠ same type
TNC p.Arg747Trp Uncertain significance ★★ ⚠ same type
TNC p.Asn507Lys Uncertain significance ★★ ⚠ same type
TNC p.Asp2059Glu Uncertain significance ★★ ⚠ same type
TNC p.Asp831Asn 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/tnc-p-arg438gln (accessed [today's date]).

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