Is TNC p.Arg608His (c.1823G>A) pathogenic?

TNC p.Arg608His (c.1823G>A) is classified Likely benign in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-28). AlphaMissense: likely benign (0.0698); Rare (popmax 0.15%, eas).

How common is TNC p.Arg608His (c.1823G>A) in the general population?

TNC p.Arg608His (c.1823G>A) is rare (popmax 0.15%, eas) (gnomAD).

What do computational predictors say about TNC p.Arg608His (c.1823G>A)?

AlphaMissense predicts likely benign (score 0.0698) — an in-silico prediction, not a clinical call.

TNC p.Arg608His

c.1823G>A · VCV4904306

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0698 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.15%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0698	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -6.80	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 -0.12	phastCons 0.45
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	15.57	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 0.15% East Asian · 67/44,806 alleles

Filtering AF 0.121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.11%

Overall 0.00546% 88/1,612,544 alleles · rare exomes 80/1,460,206 · genomes 8/152,338 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.15%	669
South Asian	0.0033%	30,315
African / African-American	0.00267%	37,514
Remaining individualsnot grpmax-eligible	0.0016%	62,378
Finnishnot grpmax-eligible	0.00156%	64,014
European (non-Finnish)	0.00119%	84,202

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.Arg608His
Coding: c.1823G>A
MANE Select: NM_002160
Type: single nucleotide variant
Location: chr9:115085908 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 608: the egf-like 15 domain

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

Similar variants

TNC p.Arg608Cys Uncertain significance ★★ ⚠ same residue
TNC p.Arg1127Trp 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
TNC p.Asp971Asn 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-arg608his (accessed [today's date]).

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