Is ROM1 p.Ser56Phe (c.167C>T) pathogenic?

ROM1 p.Ser56Phe (c.167C>T) is classified Uncertain significance in ROM1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.1562); Ultra-rare (popmax 0.0495%, mid); Associated with retinitis pigmentosa 7.

What condition is associated with ROM1 p.Ser56Phe (c.167C>T)?

ROM1 p.Ser56Phe (c.167C>T) is associated with retinitis pigmentosa 7 (ClinVar).

How common is ROM1 p.Ser56Phe (c.167C>T) in the general population?

ROM1 p.Ser56Phe (c.167C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

How is Leber congenital amaurosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ROM1 p.Ser56Phe (c.167C>T)?

AlphaMissense predicts likely benign (score 0.1562) — an in-silico prediction, not a clinical call.

ROM1 p.Ser56Phe

c.167C>T · rs199847029 · VCV498297

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1562 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

retinitis pigmentosa 7

Computational evidence

Protein change
AlphaMissense	0.1562	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -11.09	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.5	GERP 0.24, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,554 bp · p 0.86 · regional, not allelic
Overall
CADD	23.0	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 0.0495% Middle Eastern · 3/6,058 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00465% 75/1,613,104 alleles · ultra-rare exomes 66/1,460,730 · genomes 9/152,374 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
Remaining individualsnot grpmax-eligible	0.0288%	3,469
Admixed American	0.0267%	3,741
African / African-American	0.0213%	4,690
European (non-Finnish)	0.00187%	53,616

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.Ser56Phe
Coding: c.167C>T
MANE Select: NM_000327
dbSNP: rs199847029
Type: single nucleotide variant
Location: chr11:62613448 (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

Disease context

retinitis pigmentosa 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ROM1 p.Ser56Cys Uncertain significance ★★ ⚠ same residue
ROM1 p.Arg186Cys Uncertain significance ★★ ⚠ same condition
ROM1 p.Gly75Asp Uncertain significance ★★ ⚠ same condition
ROM1 p.Met271Thr Benign/Likely benign ★★ same condition
ROM1 p.Ser128fs Uncertain significance ★★ same condition
ROM1 p.Leu104fs Likely pathogenic ★ same condition
ROM1 p.Gly111fs Conflicting classifications of pathogenicity ★ same condition
ROM1 p.Leu114fs Conflicting classifications of pathogenicity ★ 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/rom1-p-ser56phe (accessed [today's date]).

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