Is REN p.Phe352Ile (c.1054T>A) pathogenic?

REN p.Phe352Ile (c.1054T>A) is classified Uncertain significance in REN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely benign (0.1263); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with REN p.Phe352Ile (c.1054T>A)?

REN p.Phe352Ile (c.1054T>A) is associated with Inborn genetic diseases (ClinVar).

How common is REN p.Phe352Ile (c.1054T>A) in the general population?

REN p.Phe352Ile (c.1054T>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about REN p.Phe352Ile (c.1054T>A)?

AlphaMissense predicts likely benign (score 0.1263) — an in-silico prediction, not a clinical call.

REN p.Phe352Ile

c.1054T>A · VCV3313607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1263 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1263	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -1.91	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 0.29	GERP -2.1
Overall
CADD	14.66	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,910 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,492 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,455
Admixed American	0.00167%	59,968

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: REN
Protein: p.Phe352Ile
Coding: c.1054T>A
MANE Select: NM_001363642 · reported on NM_000537
Type: single nucleotide variant
Location: chr1:204155825 (GRCh38)
Structure: AlphaFold pLDDT 85.00

Full REN 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

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REN p.Arg399His Uncertain significance ★★ ⚠ same condition
REN p.Gln160Arg Uncertain significance ★★ ⚠ same condition
REN p.Glu253Lys Uncertain significance ★★ ⚠ same condition
REN p.Glu310Lys Uncertain significance ★★ ⚠ same condition
REN p.Glu89Lys Uncertain significance ★★ ⚠ same condition
REN p.Gly175Val Uncertain significance ★★ 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/ren-p-phe352ile (accessed [today's date]).

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