Is TNC p.Leu148Pro (c.443T>C) pathogenic?

TNC p.Leu148Pro (c.443T>C) is classified Likely benign in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-30). AlphaMissense: likely benign (0.1004); Rare (popmax 0.317%, eas).

How common is TNC p.Leu148Pro (c.443T>C) in the general population?

TNC p.Leu148Pro (c.443T>C) is rare (popmax 0.317%, eas) (gnomAD).

What do computational predictors say about TNC p.Leu148Pro (c.443T>C)?

AlphaMissense predicts likely benign (score 0.1004) — an in-silico prediction, not a clinical call.

TNC p.Leu148Pro

c.443T>C · VCV4904326

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1004 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.317%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1004	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -4.95	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 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	16.31	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 0.317% East Asian · 141/44,520 alleles

Filtering AF 0.274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.258%

Overall 0.00915% 144/1,574,202 alleles · rare exomes 138/1,421,874 · genomes 6/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.317%	316
Remaining individualsnot grpmax-eligible	0.00494%	20,241

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.Leu148Pro
Coding: c.443T>C
MANE Select: NM_002160
Type: single nucleotide variant
Location: chr9:115090576 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB

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-leu148pro (accessed [today's date]).

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