Is LRMDA p.Ser181Phe (c.542C>T) pathogenic?

LRMDA p.Ser181Phe (c.542C>T) is classified Benign in LRMDA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0727); Common (popmax 9.87%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about LRMDA p.Ser181Phe (c.542C>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

LRMDA p.Ser181Phe

Q: How common is LRMDA p.Ser181Phe (c.542C>T) in the general population?

LRMDA p.Ser181Phe (c.542C>T) is common (popmax 9.87%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.542C>T · rs35349706 · VCV261991

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.87%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -8.22	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 4	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 1,126 kb · p 0.96 · regional, not allelic
Overall
CADD	19.54	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S153F vs ClinVar S181F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.87% African / African-American · 7,396/74,964 alleles

Filtering AF 9.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.6%

Overall 2.01% 32,412/1,614,016 alleles · common exomes 26,340/1,461,860 · genomes 6,072/152,156 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.87%	10
South Asian	6.37%	16
Remaining individualsnot grpmax-eligible	2.44%	41
East Asian	2.29%	44
Middle Eastern	2.16%	46
Admixed American	1.35%	74
European (non-Finnish)	1.29%	78
Amishnot grpmax-eligible	0.987%	101
Ashkenazi Jewishnot grpmax-eligible	0.611%	164
Finnishnot grpmax-eligible	0.515%	194

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: LRMDA
Protein: p.Ser181Phe
Coding: c.542C>T
MANE Select: NM_001305581
dbSNP: rs35349706
Type: single nucleotide variant
Location: chr10:76324426 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.40
Residue 153 UniProt numbering: a UniProt-annotated variant site (in)

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

Similar variants

LRMDA p.Arg184Cys Uncertain significance ★★ ⚠ same type
LRMDA p.Arg207His Uncertain significance ★★ ⚠ same type
LRMDA p.Met166Thr Uncertain significance ★★ ⚠ same type
LRMDA p.Tyr129Cys Uncertain significance ★★ ⚠ same type
LRMDA c.132-253009C>T Benign/Likely benign ★★ same type
LRMDA c.398+31A>C Benign ★★ same type
LRMDA c.516+53C>T Benign ★★ same type
LRMDA c.601+18T>G Likely benign ★★ 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/lrmda-p-ser181phe (accessed [today's date]).

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