Is PSPH p.Val2Ile (c.4G>A) pathogenic?

PSPH p.Val2Ile (c.4G>A) is classified Benign/Likely benign in PSPH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-27). AlphaMissense: likely benign (0.079); Common (popmax 43.8%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about PSPH p.Val2Ile (c.4G>A)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

PSPH p.Val2Ile

Q: How common is PSPH p.Val2Ile (c.4G>A) in the general population?

PSPH p.Val2Ile (c.4G>A) is common (popmax 43.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4G>A · rs77329757 · VCV1175047

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 43.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -8.09	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 3.9	GERP 4.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 9,447 bp · p 0.0022 · regional, not allelic
Overall
CADD	18.03	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 43.8% African / African-American · 21,648/49,384 alleles

Filtering AF 43.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 43.1%

Overall 6.24% 74,899/1,200,908 alleles · common exomes 49,506/1,080,356 · genomes 25,393/120,552 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	43.8%	2
East Asian	33.8%	3
South Asian	12.5%	8
Admixed American	12.3%	8
Finnishnot grpmax-eligible	10.8%	9
Middle Eastern	10.4%	10
Remaining individualsnot grpmax-eligible	6.3%	16
Ashkenazi Jewishnot grpmax-eligible	3.78%	26
Amishnot grpmax-eligible	3.62%	28
European (non-Finnish)	2.66%	38

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: PSPH
Protein: p.Val2Ile
Coding: c.4G>A
MANE Select: NM_004577
dbSNP: rs77329757
Type: single nucleotide variant
Location: chr7:56021209 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 6 PDB

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

Similar variants

PSPH p.Arg101Ter Likely pathogenic ★★ same type
PSPH c.422-3A>C Uncertain significance ★★ same type
PSPH c.570+3A>G Uncertain significance ★★ same type
PSPH c.570+5G>C Uncertain significance ★★ same type
PSPH c.*341G>A Uncertain significance ★★ same type
PSPH p.Asn124Ser Uncertain significance ★★ ⚠ same type
PSPH p.Asp32Asn Uncertain significance ★★ ⚠ same type
PSPH p.Gln204His 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/psph-p-val2ile (accessed [today's date]).

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