Is IPP p.Ala374Val (c.1121C>T) pathogenic?

IPP p.Ala374Val (c.1121C>T) is classified Uncertain significance in IPP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-16). AlphaMissense: likely benign (0.2697); Very rare (popmax 0.00229%, nfe).

How common is IPP p.Ala374Val (c.1121C>T) in the general population?

IPP p.Ala374Val (c.1121C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about IPP p.Ala374Val (c.1121C>T)?

AlphaMissense predicts likely benign (score 0.2697) — an in-silico prediction, not a clinical call.

IPP p.Ala374Val

c.1121C>T · rs762267700 · VCV2322107

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2697	likely benign
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -11.44	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.041 · regional, not allelic
Overall
CADD	32.0	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 0.00229% European (non-Finnish) · 27/1,179,494 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00174% 28/1,613,336 alleles · very rare exomes 25/1,461,158 · genomes 3/152,178 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,685
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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: IPP
Protein: p.Ala374Val
Coding: c.1121C>T
MANE Select: NM_005897
dbSNP: rs762267700
Type: single nucleotide variant
Location: chr1:45719268 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.12

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

Similar variants

IPP p.Ala203Gly Uncertain significance ★ ⚠ same type
IPP p.Ala204Val Uncertain significance ★ same type
IPP p.Ala476Val Uncertain significance ★ ⚠ same type
IPP p.Ala524Val Uncertain significance ★ same type
IPP p.Ala57Ser Uncertain significance ★ ⚠ same type
IPP p.Arg283Trp Uncertain significance ★ ⚠ same type
IPP p.Arg298Gln Uncertain significance ★ ⚠ same type
IPP p.Arg298Trp 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/ipp-p-ala374val (accessed [today's date]).

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