Is P4HTM p.Ile227Val (c.679A>G) pathogenic?

P4HTM p.Ile227Val (c.679A>G) is classified Likely benign in P4HTM (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-01). AlphaMissense: likely benign (0.1147); Low-frequency (popmax 1.67%, mid).

How common is P4HTM p.Ile227Val (c.679A>G) in the general population?

P4HTM p.Ile227Val (c.679A>G) is low-frequency (popmax 1.67%, mid) (gnomAD).

What do computational predictors say about P4HTM p.Ile227Val (c.679A>G)?

AlphaMissense predicts likely benign (score 0.1147) — an in-silico prediction, not a clinical call.

P4HTM p.Ile227Val

c.679A>G · rs140290144 · VCV2653809

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1147 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.67%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1147	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -4.55	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 4.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 17 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	17.16	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 1.67% Middle Eastern · 101/6,062 alleles

Filtering AF 1.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.3%

Overall 0.685% 11,050/1,614,058 alleles · low-frequency exomes 10,244/1,461,742 · genomes 806/152,316 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.62%	38
Middle Easterngrpmax	1.67%	60
Remaining individualsnot grpmax-eligible	0.814%	123
European (non-Finnish)	0.766%	131
Admixed American	0.545%	184
Finnishnot grpmax-eligible	0.212%	471
African / African-American	0.123%	816
South Asian	0.079%	1,265

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile227Val
Coding: c.679A>G
MANE Select: NM_177939
dbSNP: rs140290144
Type: single nucleotide variant
Location: chr3:49002551 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 1 PDB
Residue 227: an α-helix; the ef-hand 2 domain

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

Similar variants

P4HTM p.Ile227Thr Uncertain significance ★ ⚠ same residue
P4HTM p.Pro413Leu Pathogenic/Likely pathogenic ★★ same type
P4HTM p.Trp220Ter Pathogenic ★★ same type
P4HTM p.Ala233Thr Uncertain significance ★★ ⚠ same type
P4HTM p.Arg493Gln Uncertain significance ★★ ⚠ same type
P4HTM p.Ser171Gly Uncertain significance ★★ ⚠ same type
P4HTM p.Ser184Thr Uncertain significance ★★ ⚠ same type
P4HTM p.Ser269Thr 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/p4htm-p-ile227val (accessed [today's date]).

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