Is ROM1 p.Pro334Ala (c.1000C>G) pathogenic?

ROM1 p.Pro334Ala (c.1000C>G) is classified Uncertain significance in ROM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-18). AlphaMissense: likely benign (0.0591); Very rare (popmax 0.00788%, nfe).

How common is ROM1 p.Pro334Ala (c.1000C>G) in the general population?

ROM1 p.Pro334Ala (c.1000C>G) is very rare (popmax 0.00788%, nfe) (gnomAD).

What do computational predictors say about ROM1 p.Pro334Ala (c.1000C>G)?

AlphaMissense predicts likely benign (score 0.0591) — an in-silico prediction, not a clinical call.

ROM1 p.Pro334Ala

c.1000C>G · rs201291804 · VCV938056

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0591 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00788%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0591	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -7.11	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 3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,554 bp · p 0.86 · regional, not allelic
Overall
CADD	20.3	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 0.00788% European (non-Finnish) · 93/1,180,048 alleles

Filtering AF 0.00656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00608%

Overall 0.00601% 97/1,614,056 alleles · very rare exomes 94/1,461,872 · genomes 3/152,184 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00788%	12,689
Remaining individualsnot grpmax-eligible	0.0048%	20,828
African / African-American	0.00133%	74,908

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.Pro334Ala
Coding: c.1000C>G
MANE Select: NM_000327
dbSNP: rs201291804
Type: single nucleotide variant
Location: chr11:62614783 (GRCh38)
Gene constraint: LOEUF 1.003 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.56 · 1 PDB
Residue 334: the 'disordered' region

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

Similar variants

ROM1 p.Pro334Thr Uncertain significance ★★ ⚠ 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-pro334ala (accessed [today's date]).

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