Is THEM6 p.Pro51Ser (c.151C>T) pathogenic?

THEM6 p.Pro51Ser (c.151C>T) is classified Uncertain significance in THEM6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely benign (0.0955); Rare (popmax 0.129%, amr).

How common is THEM6 p.Pro51Ser (c.151C>T) in the general population?

THEM6 p.Pro51Ser (c.151C>T) is rare (popmax 0.129%, amr) (gnomAD).

What do computational predictors say about THEM6 p.Pro51Ser (c.151C>T)?

AlphaMissense predicts likely benign (score 0.0955) — an in-silico prediction, not a clinical call.

THEM6 p.Pro51Ser

c.151C>T · VCV4184043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0955 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.129%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0955	likely benign
REVEL	0.004	strongly benign-leaning
SaProt	LLR -8.52	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 -0.17	GERP -2
Regional constraint	o/e 1.01	unconstrained · MANE · 8,089 bp · p 0.8 · regional, not allelic
Overall
CADD	10.71	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 0.129% Admixed American · 75/58,230 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0967%

Overall 0.00507% 80/1,577,474 alleles · rare exomes 40/1,425,264 · genomes 40/152,210 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.129%	776
Remaining individualsnot grpmax-eligible	0.00489%	20,461
African / African-American	0.00138%	72,378
European (non-Finnish)	8.55e-05%	1,170,072

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: THEM6
Protein: p.Pro51Ser
Coding: c.151C>T
MANE Select: NM_016647
Type: single nucleotide variant
Location: chr8:142727497 (GRCh38)
Gene constraint: LOEUF 1.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.92

Full THEM6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

THEM6 p.Ala102Thr Uncertain significance ★ ⚠ same type
THEM6 p.Ala30Thr Uncertain significance ★ ⚠ same type
THEM6 p.Arg112His Uncertain significance ★ ⚠ same type
THEM6 p.Arg120Leu Uncertain significance ★ ⚠ same type
THEM6 p.Arg122His Uncertain significance ★ ⚠ same type
THEM6 p.Arg136Cys Uncertain significance ★ ⚠ same type
THEM6 p.Arg42Pro Uncertain significance ★ ⚠ same type
THEM6 p.Arg53His 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/them6-p-pro51ser (accessed [today's date]).

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