Is FRMPD4 p.Ser1237Leu (c.3710C>T) pathogenic?

FRMPD4 p.Ser1237Leu (c.3710C>T) is classified Conflicting classifications of pathogenicity in FRMPD4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-20). AlphaMissense: likely benign (0.2011); Very rare (popmax 0.00353%, sas); Associated with intellectual disability, X-linked 104.

What condition is associated with FRMPD4 p.Ser1237Leu (c.3710C>T)?

FRMPD4 p.Ser1237Leu (c.3710C>T) is associated with intellectual disability, X-linked 104 (ClinVar).

How common is FRMPD4 p.Ser1237Leu (c.3710C>T) in the general population?

FRMPD4 p.Ser1237Leu (c.3710C>T) is very rare (popmax 0.00353%, sas) (gnomAD).

What do computational predictors say about FRMPD4 p.Ser1237Leu (c.3710C>T)?

AlphaMissense predicts likely benign (score 0.2011) — an in-silico prediction, not a clinical call.

FRMPD4 p.Ser1237Leu

c.3710C>T · rs921183679 · VCV3064463

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2011 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00353%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability, X-linked 104

Computational evidence

Protein change
AlphaMissense	0.2011	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,245 bp · p 0.095 · regional, not allelic
Overall
CADD	21.9	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 0.00353% South Asian · 2/56,669 alleles

Filtering AF 0.000918% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00166% 18/1,086,194 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00353%	28,334
East Asian	0.00296%	33,797
Admixed American	0.00217%	46,081
European (non-Finnish)	0.00158%	63,192

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: FRMPD4
Protein: p.Ser1237Leu
Coding: c.3710C>T
MANE Select: NM_001368397
dbSNP: rs921183679
Type: single nucleotide variant
Location: chrX:12718536 (GRCh38)
Structure: AlphaFold pLDDT 54.86 · 5 PDB

Full FRMPD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, X-linked 104 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FRMPD4 p.Ala728Pro Uncertain significance ★★ ⚠ same condition
FRMPD4 p.Ala728Val Uncertain significance ★★ ⚠ same condition
FRMPD4 p.Ala809Thr Uncertain significance ★★ ⚠ same condition
FRMPD4 p.Arg1288Gln Uncertain significance ★★ ⚠ same condition
FRMPD4 p.Asp978Asn Uncertain significance ★★ ⚠ same condition
FRMPD4 p.Glu475Lys Uncertain significance ★★ same condition
FRMPD4 p.Gly961Glu Uncertain significance ★★ ⚠ same condition
FRMPD4 p.Leu1014Met 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/frmpd4-p-ser1237leu (accessed [today's date]).

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