Is THRAP3 p.Ser336Arg (c.1008T>G) pathogenic?

THRAP3 p.Ser336Arg (c.1008T>G) is classified Uncertain significance in THRAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.3441); Very rare (popmax 0.00653%, nfe).

How common is THRAP3 p.Ser336Arg (c.1008T>G) in the general population?

THRAP3 p.Ser336Arg (c.1008T>G) is very rare (popmax 0.00653%, nfe) (gnomAD).

What do computational predictors say about THRAP3 p.Ser336Arg (c.1008T>G)?

AlphaMissense predicts ambiguous (score 0.3441) — an in-silico prediction, not a clinical call.

THRAP3 p.Ser336Arg

c.1008T>G · VCV4184171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00653%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3441	ambiguous
REVEL	0.016	strongly benign-leaning
SaProt	LLR -7.13	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.2	GERP -3.4
Regional constraint	o/e 0.82	unconstrained · MANE · 21 kb · p 7.2e-10 · regional, not allelic
Overall
CADD	6.364	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 0.00653% European (non-Finnish) · 77/1,179,330 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.00502% 81/1,612,674 alleles · very rare exomes 78/1,460,648 · genomes 3/152,026 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00653%	15,316
Remaining individualsnot grpmax-eligible	0.0032%	31,211
African / African-American	0.00267%	37,420

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: THRAP3
Protein: p.Ser336Arg
Coding: c.1008T>G
MANE Select: NM_005119
Type: single nucleotide variant
Location: chr1:36287238 (GRCh38)
Gene constraint: LOEUF 0.244 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 46.40
Residue 336: the 'disordered' region

Full THRAP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

THRAP3 c.2647-17A>G Likely benign ★★ same type
THRAP3 p.Ala117Ser Uncertain significance ★ ⚠ same type
THRAP3 p.Ala236Val Uncertain significance ★ ⚠ same type
THRAP3 p.Ala291Val Uncertain significance ★ ⚠ same type
THRAP3 p.Ala581Thr Uncertain significance ★ ⚠ same type
THRAP3 p.Arg153Gln Uncertain significance ★ ⚠ same type
THRAP3 p.Arg156His Uncertain significance ★ ⚠ same type
THRAP3 p.Arg15Cys 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/thrap3-p-ser336arg (accessed [today's date]).

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