Is TRIP4 p.Ser8Ala (c.22T>G) pathogenic?

TRIP4 p.Ser8Ala (c.22T>G) is classified Uncertain significance in TRIP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-21). AlphaMissense: likely benign (0.059); Very rare (popmax 0.00393%, amr).

How common is TRIP4 p.Ser8Ala (c.22T>G) in the general population?

TRIP4 p.Ser8Ala (c.22T>G) is very rare (popmax 0.00393%, amr) (gnomAD).

What do computational predictors say about TRIP4 p.Ser8Ala (c.22T>G)?

AlphaMissense predicts likely benign (score 0.059) — an in-silico prediction, not a clinical call.

TRIP4 p.Ser8Ala

c.22T>G · rs1422731390 · VCV1952782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.059 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00393%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.059	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -5.60	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 0.65	GERP -3.5, phastCons 0.001
Regional constraint	o/e 0.97	unconstrained · MANE · 67 kb · p 0.41 · regional, not allelic
Overall
CADD	10.56	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 0.00393% Admixed American · 2/50,864 alleles

Filtering AF 0.000652% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000244%

Overall 0.000129% 2/1,548,302 alleles · very rare exomes 2/1,396,148 · genomes 0/152,154 · 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: TRIP4
Protein: p.Ser8Ala
Coding: c.22T>G
MANE Select: NM_016213
dbSNP: rs1422731390
Type: single nucleotide variant
Location: chr15:64387885 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.54 · 10 PDB

Full TRIP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRIP4 p.Ser8Cys Uncertain significance ★ ⚠ same residue
TRIP4 c.272-1G>T Likely pathogenic ★★ same type
TRIP4 p.Arg309Ter Pathogenic/Likely pathogenic ★★ same type
TRIP4 p.Arg466Ter Pathogenic/Likely pathogenic ★★ same type
TRIP4 p.Leu20Ter Pathogenic ★★ same type
TRIP4 p.Trp297Ter Pathogenic ★★ same type
TRIP4 p.Ala398Thr Uncertain significance ★★ ⚠ same type
TRIP4 p.Arg104Gln 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/trip4-p-ser8ala (accessed [today's date]).

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