Is P4HTM p.Val329Met (c.985G>A) pathogenic?

P4HTM p.Val329Met (c.985G>A) is classified Conflicting classifications of pathogenicity in P4HTM (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1015); Very rare (popmax 0.00441%, nfe); Associated with Inborn genetic diseases.

What condition is associated with P4HTM p.Val329Met (c.985G>A)?

P4HTM p.Val329Met (c.985G>A) is associated with Inborn genetic diseases (ClinVar).

How common is P4HTM p.Val329Met (c.985G>A) in the general population?

P4HTM p.Val329Met (c.985G>A) is very rare (popmax 0.00441%, nfe) (gnomAD).

What do computational predictors say about P4HTM p.Val329Met (c.985G>A)?

AlphaMissense predicts likely benign (score 0.1015) — an in-silico prediction, not a clinical call.

P4HTM p.Val329Met

c.985G>A · VCV4129881

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1015 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1015	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 17 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	22.3	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 0.00441% European (non-Finnish) · 52/1,179,940 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00359% 58/1,613,774 alleles · very rare exomes 56/1,461,574 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00441%	22,691
Remaining individualsnot grpmax-eligible	0.0032%	31,242
African / African-American	0.00267%	37,466
East Asian	0.00223%	44,888
South Asian	0.0011%	91,082

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: P4HTM
Protein: p.Val329Met
Coding: c.985G>A
MANE Select: NM_177939
Type: single nucleotide variant
Location: chr3:49004958 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 1 PDB
Residue 329: the fe2og dioxygenase domain

Full P4HTM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

P4HTM p.Ala233Thr Uncertain significance ★★ ⚠ same condition
P4HTM p.Arg493Gln Uncertain significance ★★ ⚠ same condition
P4HTM p.Ser171Gly Uncertain significance ★★ ⚠ same condition
P4HTM p.Ser184Thr Uncertain significance ★★ ⚠ same condition
P4HTM c.1073+105G>A Uncertain significance ★ same condition
P4HTM c.1073+16C>G Uncertain significance ★ same condition
P4HTM c.1073+36T>G Conflicting classifications of pathogenicity ★ same condition
P4HTM c.1073+38A>G Conflicting classifications of pathogenicity ★ same condition

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/p4htm-p-val329met (accessed [today's date]).

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