Is PLCE1 p.Val703Phe (c.2107G>T) pathogenic?

PLCE1 p.Val703Phe (c.2107G>T) is classified Uncertain significance in PLCE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.9029); Very rare (popmax 0.00466%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLCE1 p.Val703Phe (c.2107G>T)?

PLCE1 p.Val703Phe (c.2107G>T) is associated with Inborn genetic diseases, nephrotic syndrome, type 3 (ClinVar).

How common is PLCE1 p.Val703Phe (c.2107G>T) in the general population?

PLCE1 p.Val703Phe (c.2107G>T) is very rare (popmax 0.00466%, nfe) (gnomAD).

What do computational predictors say about PLCE1 p.Val703Phe (c.2107G>T)?

AlphaMissense predicts likely pathogenic (score 0.9029) — an in-silico prediction, not a clinical call.

PLCE1 p.Val703Phe

c.2107G>T · VCV3598618

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9029 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00466%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9029	likely pathogenic
REVEL	0.486	indeterminate
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 214 kb · p 0.44 · regional, not allelic
Overall
CADD	25.6	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 0.00466% European (non-Finnish) · 55/1,180,026 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.0039% 63/1,614,060 alleles · very rare exomes 54/1,461,856 · genomes 9/152,204 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00625%	16,012
European (non-Finnish)grpmax	0.00466%	21,455
Remaining individualsnot grpmax-eligible	0.0032%	31,243
Admixed American	0.00167%	60,002
South Asian	0.0011%	91,090

Finnish 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: PLCE1
Protein: p.Val703Phe
Coding: c.2107G>T
MANE Select: NM_016341
Type: single nucleotide variant
Location: chr10:94234205 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01 · 3 PDB
Residue 703: the ras-gef domain

Full PLCE1 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

Also linked: nephrotic syndrome, type 3

Similar variants

PLCE1 c.4506+1G>A Likely pathogenic ★★ same condition
PLCE1 c.6132+1G>A Likely pathogenic ★★ same condition
PLCE1 p.Arg1246Ter Pathogenic ★★ same condition
PLCE1 p.Arg1434Gln Likely pathogenic ★★ same condition
PLCE1 p.Arg1495Ter Pathogenic/Likely pathogenic ★★ same condition
PLCE1 p.Arg321Ter Pathogenic ★★ same condition
PLCE1 p.Arg493Ter Pathogenic ★★ same condition
PLCE1 p.Gln1020Ter Pathogenic ★★ 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/plce1-p-val703phe (accessed [today's date]).

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