Is PSMA8 p.Phe75Val (c.223T>G) pathogenic?

PSMA8 p.Phe75Val (c.223T>G) is classified Uncertain significance in PSMA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely pathogenic (0.7035); Ultra-rare (popmax 0.01%, amr).

How common is PSMA8 p.Phe75Val (c.223T>G) in the general population?

PSMA8 p.Phe75Val (c.223T>G) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about PSMA8 p.Phe75Val (c.223T>G)?

AlphaMissense predicts likely pathogenic (score 0.7035) — an in-silico prediction, not a clinical call.

PSMA8 p.Phe75Val

c.223T>G · VCV3310955

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7035 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7035	likely pathogenic
REVEL	0.238	benign-leaning
SaProt	LLR -4.64	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 58 kb · p 0.88 · regional, not allelic
Overall
CADD	27.7	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 0.01% Admixed American · 6/59,986 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000496% 8/1,613,734 alleles · ultra-rare exomes 5/1,461,534 · genomes 3/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,998
African / African-American	0.00133%	74,924
European (non-Finnish)	8.48e-05%	1,179,862

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: PSMA8
Protein: p.Phe75Val
Coding: c.223T>G
MANE Select: NM_001025096
Type: single nucleotide variant
Location: chr18:26144679 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.04

Full PSMA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PSMA8 c.230-2A>G Uncertain significance ★ ⚠ same type
PSMA8 p.Ala193Thr Uncertain significance ★ ⚠ same type
PSMA8 p.Ala211Gly Uncertain significance ★ ⚠ same type
PSMA8 p.Ala27Thr Uncertain significance ★ ⚠ same type
PSMA8 p.Ala34Val Uncertain significance ★ ⚠ same type
PSMA8 p.Arg111Cys Uncertain significance ★ ⚠ same type
PSMA8 p.Arg165Gln Uncertain significance ★ ⚠ same type
PSMA8 p.Arg7Trp 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/psma8-p-phe75val (accessed [today's date]).

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