Is PHGDH p.Ser166Pro (c.496T>C) pathogenic?

PHGDH p.Ser166Pro (c.496T>C) is classified Uncertain significance in PHGDH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely pathogenic (0.758); Very rare (popmax 8.59e-05%, nfe); Associated with PHGDH deficiency.

What condition is associated with PHGDH p.Ser166Pro (c.496T>C)?

PHGDH p.Ser166Pro (c.496T>C) is associated with PHGDH deficiency (ClinVar).

How common is PHGDH p.Ser166Pro (c.496T>C) in the general population?

PHGDH p.Ser166Pro (c.496T>C) is very rare (popmax 8.59e-05%, nfe) (gnomAD).

What do computational predictors say about PHGDH p.Ser166Pro (c.496T>C)?

AlphaMissense predicts likely pathogenic (score 0.758) — an in-silico prediction, not a clinical call.

PHGDH p.Ser166Pro

c.496T>C · rs149631480 · VCV1003912

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.758 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.59e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PHGDH deficiency

Computational evidence

Protein change
AlphaMissense	0.758	likely pathogenic
REVEL	0.61	indeterminate
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.63, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 32 kb · p 0.037 · regional, not allelic
Overall
CADD	25.0	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 8.59e-05% European (non-Finnish) · 1/1,164,138 alleles

Overall 6.92e-05% 1/1,444,540 alleles · very rare

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: PHGDH
Protein: p.Ser166Pro
Coding: c.496T>C
MANE Select: NM_006623
dbSNP: rs149631480
Type: single nucleotide variant
Location: chr1:119727088 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06 · 21 PDB
Residue 166: a turn

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

Disease context

PHGDH deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHGDH p.Ser166= Likely benign ★ same residue
PHGDH c.1078+1G>A Likely pathogenic ★★ same condition
PHGDH c.138+1G>T Likely pathogenic ★★ same condition
PHGDH c.139-2A>G Likely pathogenic ★★ same condition
PHGDH c.290+2T>C Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.357-1G>A Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.412-1G>C Likely pathogenic ★★ same condition
PHGDH c.643+1G>A Likely pathogenic ★★ 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/phgdh-p-ser166pro (accessed [today's date]).

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