Is TMEM97 p.Pro57Ser (c.169C>T) pathogenic?

TMEM97 p.Pro57Ser (c.169C>T) is classified Uncertain significance in TMEM97 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). AlphaMissense: likely benign (0.1933); Very rare (popmax 0.00127%, nfe).

How common is TMEM97 p.Pro57Ser (c.169C>T) in the general population?

TMEM97 p.Pro57Ser (c.169C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about TMEM97 p.Pro57Ser (c.169C>T)?

AlphaMissense predicts likely benign (score 0.1933) — an in-silico prediction, not a clinical call.

TMEM97 p.Pro57Ser

c.169C>T · VCV4596966

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1933	likely benign
REVEL	0.566	indeterminate
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	phastCons 0.55
Regional constraint	o/e 0.97	unconstrained · MANE · 7,550 bp · p 0.7 · regional, not allelic
Overall
CADD	18.02	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 0.00127% European (non-Finnish) · 15/1,180,032 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000929% 15/1,614,052 alleles · very rare exomes 13/1,461,890 · genomes 2/152,162 · joint denominator

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: TMEM97
Protein: p.Pro57Ser
Coding: c.169C>T
MANE Select: NM_014573
Type: single nucleotide variant
Location: chr17:28325545 (GRCh38)
Gene constraint: LOEUF 1.083 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.27
Residue 57: the expera domain

Full TMEM97 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMEM97 p.Arg140Gln Uncertain significance ★ ⚠ same type
TMEM97 p.Arg36Gly Uncertain significance ★ ⚠ same type
TMEM97 p.Arg36Leu Uncertain significance ★ ⚠ same type
TMEM97 p.Arg7Lys Uncertain significance ★ ⚠ same type
TMEM97 p.Asp122Asn Uncertain significance ★ ⚠ same type
TMEM97 p.Gln60Arg Uncertain significance ★ ⚠ same type
TMEM97 p.Ile96Val Uncertain significance ★ ⚠ same type
TMEM97 p.Leu89Ile 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/tmem97-p-pro57ser (accessed [today's date]).

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