Is PITRM1 p.Phe169Ser (c.506T>C) pathogenic?

PITRM1 p.Phe169Ser (c.506T>C) is classified Benign in PITRM1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.3243); Common (popmax 19.7%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about PITRM1 p.Phe169Ser (c.506T>C)?

AlphaMissense predicts likely benign (score 0.3243) — an in-silico prediction, not a clinical call.

PITRM1 p.Phe169Ser

Q: How common is PITRM1 p.Phe169Ser (c.506T>C) in the general population?

PITRM1 p.Phe169Ser (c.506T>C) is common (popmax 19.7%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.506T>C · rs3814596 · VCV1600892

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3243 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 19.7%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3243	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -10.35	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 35 kb · p 2.6e-05 · regional, not allelic
Overall
CADD	24.1	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 19.7% European (non-Finnish) · 231,732/1,177,022 alleles

Filtering AF 19.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.6%

Overall 18.6% 299,025/1,610,222 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	21.7%	5
Ashkenazi Jewishnot grpmax-eligible	20.3%	5
European (non-Finnish)grpmax	19.7%	5
Middle Eastern	18.3%	5
South Asian	18.2%	5
Remaining individualsnot grpmax-eligible	17.5%	6
African / African-American	14%	7
Amishnot grpmax-eligible	13.4%	7
Admixed American	9.56%	10
East Asian	5.56%	18

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PITRM1
Protein: p.Phe169Ser
Coding: c.506T>C
MANE Select: NM_014889
dbSNP: rs3814596
Type: single nucleotide variant
Location: chr10:3165440 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 169: a disulfide bond; a UniProt-annotated variant site (in)

Full PITRM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PITRM1 p.Phe169= Likely benign ★ same residue
PITRM1 p.Thr931Met Pathogenic/Likely pathogenic ★★ same type
PITRM1 p.Ala1003Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala559Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala887Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala942Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala965Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Arg32Trp 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/pitrm1-p-phe169ser (accessed [today's date]).

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