Is TNC p.Val574Met (c.1720G>A) pathogenic?

TNC p.Val574Met (c.1720G>A) is classified Likely benign in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). AlphaMissense: likely benign (0.1034); Ultra-rare (popmax 0.098%, eas).

How common is TNC p.Val574Met (c.1720G>A) in the general population?

TNC p.Val574Met (c.1720G>A) is ultra-rare (popmax 0.098%, eas) (gnomAD).

What do computational predictors say about TNC p.Val574Met (c.1720G>A)?

AlphaMissense predicts likely benign (score 0.1034) — an in-silico prediction, not a clinical call.

TNC p.Val574Met

c.1720G>A · VCV3327434

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1034 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.098%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1034	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -10.23	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 0.64
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	9.93	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 0.098% East Asian · 44/44,878 alleles

Filtering AF 0.075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0669%

Overall 0.00818% 132/1,613,970 alleles · ultra-rare exomes 127/1,461,582 · genomes 5/152,388 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.098%	1,020
Admixed American	0.00667%	14,999
European (non-Finnish)	0.00653%	15,324
Remaining individualsnot grpmax-eligible	0.0064%	15,621
South Asian	0.0022%	45,519
African / African-American	0.00133%	75,078

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.Val574Met
Coding: c.1720G>A
MANE Select: NM_002160
Type: single nucleotide variant
Location: chr9:115086011 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 574: the egf-like 14 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-val574met (accessed [today's date]).

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