Is ROM1 p.Leu129Pro (c.386T>C) pathogenic?

ROM1 p.Leu129Pro (c.386T>C) is classified Uncertain significance in ROM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-30). AlphaMissense: ambiguous (0.344); Very rare (popmax 0.000339%, nfe).

How common is ROM1 p.Leu129Pro (c.386T>C) in the general population?

ROM1 p.Leu129Pro (c.386T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ROM1 p.Leu129Pro (c.386T>C)?

AlphaMissense predicts ambiguous (score 0.344) — an in-silico prediction, not a clinical call.

ROM1 p.Leu129Pro

c.386T>C · rs1477494423 · VCV1431941

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.344 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.344	ambiguous
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -13.62	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,554 bp · p 0.86 · regional, not allelic
Overall
CADD	25.4	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 0.000339% European (non-Finnish) · 4/1,179,924 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,000 alleles · very rare exomes 4/1,461,694 · genomes 0/152,306 · joint denominator

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: ROM1
Protein: p.Leu129Pro
Coding: c.386T>C
MANE Select: NM_000327
dbSNP: rs1477494423
Type: single nucleotide variant
Location: chr11:62613667 (GRCh38)
Gene constraint: LOEUF 1.003 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.56 · 1 PDB

Full ROM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ROM1 p.Leu129= Likely benign ★ same residue
ROM1 p.Ala132Val Uncertain significance ★★ ⚠ same type
ROM1 p.Ala140Thr Uncertain significance ★★ ⚠ same type
ROM1 p.Ala265Thr Uncertain significance ★★ ⚠ same type
ROM1 p.Ala329Val Uncertain significance ★★ ⚠ same type
ROM1 p.Ala54Thr Uncertain significance ★★ ⚠ same type
ROM1 p.Ala69Gly Uncertain significance ★★ ⚠ same type
ROM1 p.Ala71Thr 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/rom1-p-leu129pro (accessed [today's date]).

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