Is TNC p.Arg438Trp (c.1312C>T) pathogenic?

TNC p.Arg438Trp (c.1312C>T) is classified Likely benign in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-01). AlphaMissense: likely benign (0.1725); Ultra-rare (popmax 0.0165%, mid).

How common is TNC p.Arg438Trp (c.1312C>T) in the general population?

TNC p.Arg438Trp (c.1312C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TNC p.Arg438Trp (c.1312C>T)?

AlphaMissense predicts likely benign (score 0.1725) — an in-silico prediction, not a clinical call.

TNC p.Arg438Trp

c.1312C>T · rs771475685 · VCV810409

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1725 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1725	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -11.03	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	phastCons 0.79
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	25.2	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00527% 85/1,612,762 alleles · ultra-rare exomes 77/1,461,690 · genomes 8/151,072 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
African / African-American	0.00806%	12,413
Remaining individualsnot grpmax-eligible	0.0064%	15,615
European (non-Finnish)	0.00551%	18,149
South Asian	0.00549%	18,206
Admixed American	0.00501%	19,973
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594

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.Arg438Trp
Coding: c.1312C>T
MANE Select: NM_002160
dbSNP: rs771475685
Type: single nucleotide variant
Location: chr9:115086419 (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.Arg438Gln Uncertain significance ★ ⚠ 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-arg438trp (accessed [today's date]).

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