Is THBD p.Arg322Leu (c.965G>T) pathogenic?

THBD p.Arg322Leu (c.965G>T) is classified Conflicting classifications of pathogenicity in THBD (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-01). AlphaMissense: likely benign (0.1268); Ultra-rare (popmax 0.0427%, afr); Associated with THBD-related disorder.

What condition is associated with THBD p.Arg322Leu (c.965G>T)?

THBD p.Arg322Leu (c.965G>T) is associated with THBD-related disorder, atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Arg322Leu (c.965G>T) in the general population?

THBD p.Arg322Leu (c.965G>T) is ultra-rare (popmax 0.0427%, afr) (gnomAD).

What do computational predictors say about THBD p.Arg322Leu (c.965G>T)?

AlphaMissense predicts likely benign (score 0.1268) — an in-silico prediction, not a clinical call.

THBD p.Arg322Leu

c.965G>T · rs146549103 · VCV896683

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1268 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0427%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

THBD-related disorder

Computational evidence

Protein change
AlphaMissense	0.1268	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -7.84	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 -3.6	GERP -2.9
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	12.21	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 0.0427% African / African-American · 32/74,934 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00231% 37/1,600,376 alleles · ultra-rare exomes 22/1,448,154 · genomes 15/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0427%	2,342
Remaining individualsnot grpmax-eligible	0.00642%	15,579
European (non-Finnish)	8.48e-05%	1,179,660

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.Arg322Leu
Coding: c.965G>T
MANE Select: NM_000361
dbSNP: rs146549103
Type: single nucleotide variant
Location: chr20:23048540 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 322: the egf-like 2 domain

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

Disease context

THBD-related disorder

Also linked: atypical hemolytic-uremic syndrome with thrombomodulin anomaly

Similar variants

THBD p.Arg322Gln Uncertain significance ★ ⚠ same residue
THBD p.Arg322= Likely benign ★ same residue
THBD p.Cys537Ter Pathogenic/Likely pathogenic ★★ same condition
THBD p.Ala139Ser Uncertain significance ★★ ⚠ same condition
THBD p.Ala284Gly Uncertain significance ★★ ⚠ same condition
THBD p.Ala395Val Uncertain significance ★★ ⚠ same condition
THBD p.Ala471Thr Uncertain significance ★★ ⚠ same condition
THBD p.Ala545Thr 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-arg322leu (accessed [today's date]).

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