Is THBD p.Leu102Phe (c.304C>T) pathogenic?

THBD p.Leu102Phe (c.304C>T) is classified Uncertain significance in THBD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-30). AlphaMissense: likely benign (0.087); Very rare (popmax 0.00351%, sas); Associated with Inborn genetic diseases.

What condition is associated with THBD p.Leu102Phe (c.304C>T)?

THBD p.Leu102Phe (c.304C>T) is associated with Inborn genetic diseases (ClinVar).

How common is THBD p.Leu102Phe (c.304C>T) in the general population?

THBD p.Leu102Phe (c.304C>T) is very rare (popmax 0.00351%, sas) (gnomAD).

What do computational predictors say about THBD p.Leu102Phe (c.304C>T)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

THBD p.Leu102Phe

c.304C>T · rs1207535395 · VCV2293083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00351%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP -1.7
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	3.988	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 0.00351% South Asian · 3/85,382 alleles

Filtering AF 0.000933% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000459%

Overall 0.00032% 5/1,562,600 alleles · very rare exomes 5/1,410,260 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00351%	28,461
Remaining individualsnot grpmax-eligible	0.0033%	30,270

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: THBD
Protein: p.Leu102Phe
Coding: c.304C>T
MANE Select: NM_000361
dbSNP: rs1207535395
Type: single nucleotide variant
Location: chr20:23049201 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 102: the c-type lectin domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

THBD p.Ala21Ser Uncertain significance ★★ ⚠ same condition
THBD p.Ala255Pro Uncertain significance ★★ ⚠ same condition
THBD p.Ala272Val Uncertain significance ★★ ⚠ same condition
THBD p.Arg264His Uncertain significance ★★ ⚠ same condition
THBD p.Arg567Gln Uncertain significance ★★ ⚠ same condition
THBD p.Arg83Gly Uncertain significance ★★ ⚠ same condition
THBD p.Asn115Asp Uncertain significance ★★ ⚠ same condition
THBD p.Asn128Ser Uncertain significance ★★ ⚠ same condition

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/thbd-p-leu102phe (accessed [today's date]).

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